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1
Vuljan, Stefania Edith. "Idiopathic Pulmonary Fibrosis (IPF): tissue identification of crucial biomarkers by RNA-Sequencing approach." Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3422229.
Full textAbstract:
Background. Idiopathic pulmonary fibrosis (IPF) is one of the most common idiopathic interstitial lung diseases characterized by progressive lung scarring and a very poor overall prognosis with a median survival of 2-3 years. Despite extensive research efforts, the etiopathogenesis and pathophysiology of IPF are still little understood and consequently only slight improvement has been made for appropriate management and effective therapies. Some advances have been made in understanding the multiple interrelated pathogenic pathways underlying IPF and the disease is now considered to result from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic and environmental factors. Thus, the discovery and validation of theranostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve the prediction of future disease behavior. Usual interstitial pneumonia (UIP) is the histopathological pattern of IPF characterized by spatial/temporal heterogeneous histological lesions. Fibroblastic focus (FF) areas include fibroblasts and myofibroblasts arranged in a linear fashion with a pale staining matrix, with metaplastic epithelial cells lining on top of them. They are usually detected in the transitional area from dense scarring to normal lung and are considered an “active” component in IPF pathogenesis.
Aim of the research. The main goal of the present PhD research project was the identification of crucial biomarkers in IPF pathogenesis by extracting RNA from FF areas (FF plus metaplastic epithelial cells lining FF). The main steps of the study were the following:
1) validation of a protocol for the isolation of FF areas by laser microdissection of formalin-fixed and paraffin-embedded (FFPE) tissues of IPF patients and controls;
2) total RNA extraction, quality and quantity evaluation;
3) creation of cDNA libraries starting from the extracted RNAs;
4) transcriptomic analysis by a Next-Generation Sequencing (NGS) approach (RNA-sequencing; RNA-Seq);
5) validation of the biomarker emerged from the transcriptomic analysis in a more extensive (retrospective) cases series using immunohistochemistry.
Material and Methods. Total RNA was extracted from fibroblastic focus areas isolated with laser microdissection in 10 FFPE IPF lung tissues: 8 from lung transplanted patients and 2 from surgical biopsy. Microdissected fibroblastic focus areas from 2 patients with recurrent pneumothorax were also analyzed and considered as controls. The RNA was extracted using a modified protocol which provides an overnight tissue incubation at 43°C with 10 μl proteinase K. RNA was then preserved by adding RNase inhibitors at the end of the extraction procedure. This was a custom-made protocol (RNeasy® FFPE kit; Qiagen, Hilden, Germany) with additional procedures optimized during my PhD research study. The final RNAs quality and quantity were valuated with an Agilent RNA 6000 Pico Kit using a 2100 Bioanalyzer instrument. Quality was expressed as DV200 (percentage of RNA fragments > 200 nucleotides). Libraries were obtained with the SMARTer Stranded Total RNA-Seq Kit pico input mammalian of Takara Bio. DNA library was sequenced with a paired-end sequencing 2x150 bp on a HiSeq 4000 System sequencer of Illumina. MUC5B immunohistochemistry (clone 4A10-H2; 1:200, Novus Biologicals, Centennial, Colorado, USA) was performed in 44 interstitial lung disease (ILD) cases (39 UIP/IPF and 5 ILD with no UIP pattern) and 6 controls (5 spontaneous pneumothorax and 1 emphysema) following the antibody manufacturer's protocol using a Leica Bond-III Autostainer.
Results. Considering the whole population the mean quantity of extracted RNA was 2992.8 pg/µl±2473 (mean ± SD), ranging from 840 pg/µl to 7530 pg/µl. Quality evaluation showed 42% of total cases with a medium/high quality (DV200>50%). In all cases molecular analyses were performed and final libraries were obtained with a concentration ranging from 3.4 to 22.6 ng/ul and a mean cDNA fragment length of 289 nucleotides. RNA-Seq analysis showed that 323 genes were differentially expressed in UIP/IPF cases than controls: 14 of them were up-regulated and 309 down-regulated. The most significant up-regulated gene was MUC5B, the other up-regulated genes were those involved in epithelial-to-mesenchymal transition (EMT) and epithelial carcinogenesis process. Gene Ontology Enrichment Analysis (GOEA) was performed to identify the most enriched Gene Ontology (GO) categories for the down-regulated genes. We found that extracellular matrix structure and organization were the principally down-regulated pathways.
The overexpressed gene MUC5B was validated by immunohistochemistry. MUC5B was expressed only in IPF/UIP and ILDs, never in control group. The MUC5B expression was mainly detected in metaplastic epithelial cells lining: a) honeycomb areas, b) other alveolar spaces and c) in the metaplastic epithelial cells lining FF. Interestingly, a gradient of MUC5B expression was detected both in IPF/UIP and ILDs samples where MUC5B was overexpressed in lower lobes. Interestingly, MUC5B was overexpressed in upper and middle lobes of IPF/UIP compared with the same lobes of other ILDs.
Conclusion. The principal results obtained from the present research study offer interesting insights into the complex molecular system signature of IPF:
1) adequate quantity and quality of RNA was extracted from microdissected FF areas of FFPE IPF lung tissues. The quantity/quality of RNA was suitable to create cDNA libraries for transcriptomic analysis by RNA-seq: this represents an important step forward in tissue molecular investigation of this disease characterized by high tissue heterogeneity. Only a very few papers in the literature have used lung FFPE tissue for molecular analysis, in particular, this molecular approach on specific affected IPF tissues has not previously used.
2) Comparative analysis performed on selected areas found an overexpression of epithelial proliferation/cancer progression and EMT transcripts: this highlights the crucial role of metaplastic epithelial cells that are the key actors also in the FF areas, considered the active injured lesion in IPF.
3) The up-regulated transcript MUC5B, validated also by immunohistochemistry, confirms the crucial role of this mucin in the disease. Indeed previous works, mainly performed in blood samples, had highlighted the importance of this gene in the disease. Selective regulation of MUC5B in experimental models could open up an entire line of investigation that could bring us closer to understanding regulation of MUC5B and providing novel therapeutic options.
2
FRAGNI, DEBORA. "Identification of novel readouts to assess anti-fibrotic efficacy of new compounds in a bleomycin-induced pulmonary fibrosis mouse model." Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1190103.
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Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and very limited therapeutic options. To date, Pirfenidone and Nintedanib are the only two therapies approved for IPF worldwide. However, these drugs can slow-down lung function decline without really stopping or reverting the fibrotic process, and in addition their use is associated with a series of side effects. The incomplete understanding of the disease and the limitations of current treatments make IPF a disease with a high medical need requiring novel treatment approaches. For these reasons, the new drugs coming from the research and development pipelines will be crucial to get new treatments for patients.
Despite widely used, the current animal models of IPF need to be improved in order to be as much predictive as possible in identifying new promising treatments for pulmonary fibrosis. One of the most challenging aspects of drug discovery for IPF is the identification of new therapies that can be translated effectively to the clinic, implying that very few compounds that have shown efficacy in animal models have been successful in human clinical trials and concluding that most of the preclinical models are poorly predictive and scarcely resembling the human disease. Currently the majority of new drugs investigated in preclinical models of IPF are dosed using a prophylactic dosing regimen, whereas patients are almost always treated after the fibrosis is well established. Moreover, the most popular endpoints examined in preclinical models of IPF are histological scoring and lung collagen content; however, lung function tests are more commonly used as primary endpoints in IPF patients.
In this scenario, considering the high unmet medical need and some limits that the preclinical research has to face, the main goal of this PhD project was to generate a robust and reliable preclinical model of pulmonary fibrosis, introducing novel readouts, suitable to select and to identify new pharmacological treatments for IPF with an higher translational potential. The approach pursued by this study could be very impactful to identify new potential treatments for IPF. To achieve the goal of this PhD project, performed in collaboration with Chiesi Farmaceutici, we (1) reproduced the most described preclinical model for IPF, the bleomycin (BLM)-induced pulmonary fibrosis mouse model by intratracheal (IT) administration, and we analyzed its main limitations; (2) looking at the clinic, we optimized the BLM model with the introduction of clinically more relevant parameters (i.e., lung function tests, lung imaging, oximetry (Sp02), and fibrotic biomarkers) through a new BLM oropharyngeal (OA) protocol and finally, (3) we explored the added value of these more relevant readouts by investigating the efficacy of Nintedanib, which was tested under therapeutic regimen.
The characterization of the BLM IT model proved to be useful in better understanding the development of BLM-induced lung fibrosis and allowed to define the therapeutic protocol to test the anti-fibrotic efficacy of Nintedanib in the model; however, it highlighted several limitations such as a patchy distribution of fibrotic lesions and poor sensitivity to pharmacological treatment using the two traditional preclinical readouts, histology and hydoxyproline (Hyp) lung content.
Those limitations were overcome by the use of the OA administration of BLM which led to a more homogeneous fibrosis throughout the lung lobes and by the introduction of more clinically relevant endpoints such as micro-computer tomography (CT) imaging and lung function measurements that are the same tests used to diagnose and monitor patients with IPF, as well as of emerging biomarkers currently under evaluation in the clinical setting, with the final aim to create a link between the preclinical model and the clinical practice. All these new readouts showed the same profile over time observed with histology in terms of development of fibrotic disease, and Nintedanib was able to significantly modulate them, confirming their relevance for monitoring lung fibrosis as well as the efficacy of new treatments. Among them, the measurement of lung function, in particular the forced vital capacity (FVC), demonstrated to be the most sensitive readout to assess the compounds efficacy and was selected also in our preclinical studies as the primary endpoint as for clinical trials, thus creating an important link between the preclinical model and the clinical setting.
In addition, we also worked to refine the histological analysis which still remains an important complementary evaluation to be coupled to the functional readouts. Currently the common histological analysis utilized in preclinical models of lung fibrosis is represented by the Ashcroft scoring system, which revealed some disadvantages such as a time-consuming process, operator-dependent results, limited sensitivity and, most critical, inability to get a direct link to clinics. Therefore, we introduced an automated image analysis by using an artificial intelligence (AI) approach, which improved this analysis recognizing histological features with more accuracy and consistency, reducing significantly the time of the analysis and making the evaluation independent from the operator.
In summary, this project demonstrated that in the mouse BLM-induced lung fibrosis model it has been possible to explore the same clinically relevant parameters used in IPF patients; in particular lung function tests such as FVC, that for its high translational value together with the high sensitivity to assess the efficacy of the compounds has been chosen as the primary endpoint to support the selection of novel treatments within our internal drug discovery IPF projects. Furthermore, the introduction of these different readouts, that all go to the same direction, has from one side increased the robustness of the model and from the other side has allowed to bring this preclinical model to a level of complexity that mirrors the one observed in human IPF.
Overall, this PhD work has enhanced the translational value of the data obtained with the mouse BLM model increasing the chance of selecting promising compounds to advance to clinical trials and has concretely led to significant benefits to drug discovery process in the IPF research, improving the quality and the reliability of the search of novel anti-fibrotic drugs.
3
Fahim, Ahmed. "The pathogenesis of idiopathic pulmonary fibrosis." Thesis, University of Hull, 2011. http://hydra.hull.ac.uk/resources/hull:5296.
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Idiopathic pulmonary fibrosis (IPF) is a restrictive pulmonary disorder of unknown aetiology with a relentless disease course and a median survival of 3 years after the diagnosis. It is the most common idiopathic interstitial lung disease (ILD) with a basal and peripheral predominance associated with temporal and geographical heterogeneity. As the pathogenesis of this disease is poorly understood, the aim of this work was to investigate the pathobiology of IPF in a prospective manner. There is evidence of a strong association of gastro-esophageal reflux and vascular disease with IPF. Moreover, a proportion of patients have evidence of immunological antibodies without any evidence of connective tissue or autoimmune disease. The data presented in this thesis suggest that platelet-monocyte complexes may be involved in the pathogenesis of IPF at molecular level as suggested by the flow cytometric data utilizing monoclonal antibodies to platelets (CD42a) and monocytes (CD14). Moreover, expression of CD40L, P-selectin and PSGL-1 on platelets and subpopulation of leukocytes suggested that platelet expression of these molecules is not significantly different in IPF as compared to ILD other than IPF or non-ILD controls. Furthermore, platelet mediated injury hypothesis is supported by significant elevation of platelet endothelial cell adhesion molecule in plasma of IPF patients. Reflux of gastric secretions into the tracheo-bronchial tree is another attractive hypothesis in light of remarkably high prevalence of gastro-esophageal reflux disease (GERD) in IPF. The data suggest that patients with IPF have significantly higher gastro and extra-esophageal reflux symptoms when assessed by Hull airway reflux questionnaire (HARQ). However, there was a lack of objective evidence of extra-esophageal reflux measured by exhaled breath pepsin concentration or significantly higher prevalence of Helicobacter Pylori. Furthermore, there was evidence of immune mediated injury in IPF by indirect immunofluorescence study of alveolar epithelial (A549) cells as significant membranous enhancement of A549 cells by anti-IgG antibodies was demonstrated in IPF patients’ sera. However, Human umbilical vein endothelial cells (HUVEC) did not show any differential staining pattern with either anti-IgG or IgM. Hence, there is a suggestion of alveolar epithelial disruption mediated by immune mechanisms with a predominant involvement of IgG antibodies. Furthermore, epithelial derangement may extend into the respiratory epithelium with release of carcinoembryonic antigen (CEA) in peripheral circulation as evidenced by a significant correlation of raised CEA level and lung function impairment in IPF. These findings provide clinical and molecular evidence of novel mechanisms of pathogenesis of IPF with increased platelet-monocyte aggregation. Moreover, immune mediated alveolar epithelial dysfunction involving IgG antibodies may provide further insight into the understanding of the pathogenesis and natural history of this fibrotic disease.
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Jo, Helen Eun-Ae. "Predicting Prognosis in Idiopathic Pulmonary Fibrosis." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20029.
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Idiopathic pulmonary fibrosis (IPF) is a specific fibrosing, interstitial lung disease (ILD) of unknown aetiology. In recent years, immunosuppressive therapy, used for the treatment of a majority of ILDs has been shown to be harmful in IPF, while new antifibrotic treatments that can slow IPF progression have become widely available. The accurate distinction of IPF from other ILDs has therefore become of utmost importance as it has important managements and prognostic implications. While the prognosis of IPF is universally poor with a median survival of only 3-5 years, the disease course is heterogeneous with some patients having rapidly progressive disease, while other have slow progression. In many patients, there are periods of stability interspersed with periods of rapid progression however at present, it is not possible to predict a patient’s disease course. The main objective of this thesis is to find factors that predict the prognosis in patients with IPF. In order to achieve this objective, this thesis is divided into two main sections. In the first section, we concentrate on the ILD multidisciplinary meeting (MDM). The diagnosis of IPF can often be challenging as it shares many clinical, radiological and histopathological features with the other ILDs. A multidisciplinary discussion between clinicians, radiologist and histopathologists is therefore recommended for accurate diagnosis. Unfortunately, there is no “gold standard” for IPF diagnosis and while significant emphasis is placed on the importance of the ILD MDM, there is little to actually guide the structure and function, or to standardise the output of this diagnostic process. In Chapter 2 of this thesis, we survey expert ILD MDMs internationally to assess current practices and find features common to most MDMs. We also assess features that differ and may potentially result in bias and thus inconsistencies in the performance of ILD MDMs. We introduce suggestions based on our findings that may be core features to the development of MDMs (presence of core clinical groups, structure and frequency of meetings) and areas that require consideration and further assessment as to their potential impact. In Chapter 3, we assess the impact of the ILD multidisciplinary service at 2 Australian centres and find there is a significant impact on IPF diagnosis and thus subsequent management. This section of the thesis therefore highlights the fact that before we can explore features that predict prognosis in IPF, we must also improve methods by which IPF is diagnosed as this can be difficult and result in inaccuracies when predicting prognosis and instituting therapies for IPF. In Chapters 4 to 8 of this thesis we concentrate on clinical, physiological and radiological factors that predict prognosis in IPF patients. Using the Australian IPF Registry, we find that more severe physiological impairment, as well as higher symptoms scores at baseline are associated with worse prognosis. We also find however, that the progression of disease in patients with mild physiological impairment, measured as an annual decline in FVC % predicted, is the same in those with mild and more severe impairment. This suggests that the worse prognosis in those with greater physiological impairment may be related to patients being at a later stage of IPF disease. We also find that the presence of honeycombing on radiology, but not the classification of the radiological UIP pattern, predicts poorer prognosis and that the presence or treatment of gastroesophageal reflux disease has no impact of IPF outcomes. Overall, this thesis has contributed to the field by highlighting the impact of the ILD MDM and assessing features that may contribute to accuracy of diagnosis and subsequent prognosis of IPF. We also found factors that predict IPF prognosis in real-world cohorts. While these results are useful and at times, reinforce factors that have been found in other IPF cohorts, the ability to accurately diagnose and predict the IPF course of an individual patient remains elusive. Further studies, particularly focusing on the pathobiology of IPF and translation to potential biomarkers are needed in order to improve and refine our understanding of the factors that predict prognosis in IPF.
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Hutchinson, Nicola-Xan. "Studies of cough in Idiopathic Pulmonary Fibrosis." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/94471/.
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A dry cough is a common symptom described in patients with IPF and impairs quality of life. The exact mechanisms causing cough in IPF remain unclear, however there is evidence that altered cough neurophysiology and sensitisation plays a roleY IPF patients have an enhanced cough reflex sensitivity to the inhalation of capsaicin. It was hypothesised that IPF patients have increased airway expression of the capsaicin receptor TRPVF1 and a coFexpressed receptor TRPAF1. Bronchial biopsies were obtained in 16 IPF patients, 11 chronic cough patients and 8 controls. Quantitative PCR was used to detect TRPVF1 and TRPAF1 gene expression, with immunohistochemistry demonstrating protein expression. Mean TRPVF1 and TRPAF1 gene expression was higher in IPF patients compared with controls, but the difference did not reach statistical significance. Immunostaining supported these findings. Gastroesophageal reflux is common in IPF patients and has also been implicated. An inFvitro study using cultured pulmonary epithelial cells was conducted to assess the expression of these receptors in a cell model of gastric reflux. TRPVF1 and TRPAF1 gene expression was demonstrated in pulmonary epithelial cells of bronchial and alveolar origin. No significant difference in receptor expression level was seen in either cell line when exposed to the major constituents of gastric refluxate. This study suggests that a structural upFregulation of central airway TRP receptors is not the key mechanism for cough in IPF patients. Similarly, it does not support the role of the individual constituents of gastric refluxate resulting in cough hypersensitivity through a physical upFregulation of receptors in pulmonary epithelial cells. Overall this thesis outlines the complexity of the cough reflex. It is probable that cough in IPF results from the cumulative manifestation of various physiological changes and mechanisms.
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Hutchinson, John. "International comparative epidemiology of idiopathic pulmonary fibrosis." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/40715/.
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Background Evidence from the UK suggests the incidence of idiopathic pulmonary fibrosis is increasing, but there is a lack of data from elsewhere in the World. The cause of the disease remains unknown. New anti-fibrotic therapies may increase the use of surgical lung biopsy for accurate diagnosis, although the risks of this (and other surgery) are not clear. Methods Collated international mortality statistics and a systematic review of the literature were used to assess the incidence and mortality of idiopathic pulmonary fibrosis worldwide. Primary care data from the United Kingdom were used to assess the association between recent major surgery and a new diagnosis of idiopathic pulmonary fibrosis. Secondary care data from the United States and United Kingdom were used to assess the risk of surgical lung biopsy for the diagnosis of interstitial lung disease, and the risk of other major surgery in those with idiopathic pulmonary fibrosis. Results Mortality from idiopathic pulmonary fibrosis in increasing steadily worldwide. Incidence varies worldwide but is in the range of 3-9 per 100,000 in the West. No association was identified between recent major surgery and a new diagnosis of idiopathic pulmonary fibrosis. Surgical lung biopsy for the diagnosis of interstitial lung disease has an in-hospital mortality of under 2% for elective procedures, but this is higher for non-elective surgery, and in those who are older with co-morbidities. In those with idiopathic pulmonary fibrosis undergoing major surgery, in-hospital mortality was higher than the general population. Conclusion Idiopathic pulmonary fibrosis seems to be increasingly common worldwide. Surgery has risks, particularly in unwell older patients, and less invasive diagnostic methods are needed.
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Luk, Sheung Fung Simon. "Alveolar macrophage heterogeneity in idiopathic pulmonary fibrosis." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/29433.
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Idiopathic Pulmonary Fibrosis (IPF) involves excess extracellular matrix (ECM) deposition within the lung interstitium, caused by non-resolving chronic inflammation and dysregulated repair. Alveolar macrophage (AMφ) may contribute to IPF through releasing various mediators by different subsets, investigated here in vitro, and ex vivo using a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. The role of foamy AMφ in the reported increased susceptibility of Hermansky Pudlak Syndrome (HPS) 1 mice to BLM-induced pulmonary fibrosis was also assessed. Novel characterisation studies revealed that terminally differentiated AMφ are inducible into M1-like [nitric oxide synthase 2 (NOS2)hi interleukin (IL)-1βhi IL-12 p40 (total)hi major histocompatibility protein (MHC)-IIhi mannose receptor C, type 1 (MRC1)-] or M2-like [Arginase 1 (Arg1)hi Fibronectinhi IGF-1hi MHC-IIlo MRC1-/+] phenotypes following IFN-γ or IL-13 priming respectively. Lipopolysccharide (LPS) altered these AMφ subset phenotypes. AMφ heterogeneity in a novel multiple oropharyngeal dose, BLM-induced pulmonary fibrosis was evaluated from days 7 to 21. Accumulation of M1-like AMφ at day 7, and M1/M2-hybrid AMφ [Arg1hi IL-12 p40 (total)hi fibronectinhi MHC-IIlo MRC1-/+] from days 7 to 21, may promote inflammation and fibrosis respectively. Toll-like Receptor (TLR) 9 messenger ribonucleic acid (mRNA) and TLR2 surface protein, and both TLRs2 and 9 ex vivo activities were increased in BLM-challenged mice from days 7 to 21, suggesting their roles in inflammation and fibrosis. Foamy AMφ accumulated in BLM-induced pulmonary fibrosis, and their potential role in the reported increased susceptibility to BLM-induced pulmonary fibrosis of HPS1 mice was evaluated. BLM-challenged HPS1 mice (days 7-21) had increased weight loss indicating reduced BLM tolerance from days 7 to 11, but little/no difference in collagen accumulation, suggesting that reduced BLM tolerance is not correlated with increased pulmonary fibrosis. In conclusion AMφ alter their phenotype in response to their environment that contributes to different stages of BLM-induced pulmonary fibrosis. Reduced BLM tolerance in HPS1 mice is not correlated with increased pulmonary fibrosis.
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Maduli, Elvis. "Polypharmacology approaches for treatment of idiopathic pulmonary fibrosis." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/15540/.
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Patrucco, Filippo. "Idiopathic pulmonary fibrosis: from monocyte and macrophage inflammation to a novel, non-invasive measurement of pulmonary density." Doctoral thesis, Università del Piemonte Orientale, 2022. http://hdl.handle.net/11579/144064.
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The anti-fibrotic drug nintedanib (NTD) has been approved for the management of Idiopathic Pulmonary Fibrosis (IPF), a rare progressive interstitial lung disease. Monocytes/macrophages and alveolar macrophages have been demonstrated to contribute to the wound healing process, promoting inflammation and collagen deposition. Aim: We intend to evaluate the effects of NTD on phenotype and responsiveness of monocytes/macrophages isolated from IPF patients before (TO) and after 3 months of treatment
(T1) with the drug. In this thesis the results obtained from patients at TO will be showed. Samples from healthy volunteers and from patients will be challenged in vitro with NTD. Methods: Monocytes were isolated from peripheral blood and differentiated into M1 and M2 macrophages; cell viability, superoxide anion production and surface markers expression were evaluated. Results: we included 10 IPF patients and 5 healthy volunteers. For in vitro experiments, we used increasing concentrations of NTD up to the highest of 15nM. In monocytes from both healthy
volunteers and patients NTD reduced the basal production of superoxide anion and at 15nM the effect was similar in both populations. After NTD treatment we observed a reduction of non classical monocytes percentage, with a relative reduction of classical monocytes. NTD did not significantly affect the basal 02- production in M1 neither in M2, but it reduced in a dose dependent manner the PMA-induced burst in both macrophage populations. Among surface markers' expression, we observed a reduction of CD206 in M2 macrophages of IPF subjects after NTD stimulation. Conclusions: Our results could build the basis to verify if in IPF patients monocyte production of oxidative stress would influence macrophages polarization, and to support the antifibrotic effects of NTB also by the reduction of CD206 profibrotic marker expression in M2 cells.
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Duffy, Emma. "Approaches to lead generation for idiopathic pulmonary fibrosis targets." Thesis, University of Strathclyde, 2016. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27489.
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Ikezoe, Kouhei. "Bone mineral density in patients with idiopathic pulmonary fibrosis." Kyoto University, 2016. http://hdl.handle.net/2433/215403.
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Final publication is avilable at http://www.sciencedirect.com/science/article/pii/S0954611115300172Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19577号
医博第4084号
新制||医||1013(附属図書館)
32613
京都大学大学院医学研究科医学専攻
(主査)教授 伊達 洋至, 教授 平家 俊男, 教授 松田 秀一
学位規則第4条第1項該当
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Allen, Richard James. "Shared and distinct genetic determinants between idiopathic pulmonary fibrosis and other pulmonary traits." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42483.
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Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by the deposit of scar tissue on the lung epithelium, reduced lung function and poor prognosis (median survival 3 years). Despite environmental and genetic factors being reported as associated with IPF, the pathogenesis of IPF is unclear and few effective treatment options are available. If the genetic basis of IPF were shared with another trait then this may aid understanding of the disease and guide research into new treatments. The aims of this thesis are to investigate variants associated with IPF and to analyse genetic overlap between IPF and other pulmonary traits. A two-stage genome-wide case-control analysis replicated previously reported signals as associated with IPF susceptibility and highlighted a novel signal near AKAP13. Functional follow-up suggests this signal increases IPF susceptibility by increased expression of AKAP13 in a tissue specific manner. This is the first time a gene in a fibrotic pathway has been implicated in an IPF genome-wide study. Furthermore, this pathway is therapeutically targetable. The first genome-wide analysis into survival time after diagnosis of IPF was also performed and highlighted 34 variants of interest. The variant showing the strongest IPF susceptibility association (in the promoter of MUC5B) showed some association with increased survival times. Finally, genetic overlap of IPF and other pulmonary traits was explored. There was little genetic overlap between IPF susceptibility and survival suggesting variants that increase susceptibility are different to those driving disease progression. Some genetic overlap was observed between variants highly associated with IPF and airflow in the lungs. Finally, the thesis provides evidence that IPF is polygenic, albeit with a small number of associated variants exhibiting a relatively large effect on disease susceptibility.
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Biondini, Davide. "From cigarette smoking to Chronic Obstructive Pulmonary Disease or Idiopathic Pulmonary Fibrosis. Why?" Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3423181.
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Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are two chronic lung diseases with distinct clinical, pathological and epidemiologic features. In both disorders cigarette smoking represents a major risk factor; indeed, it causes a repetitive alveolar damage that elicit inflammatory response and may enhance the establishment of the disease. During my PhD, we investigated the role of innate and adaptive immune response in COPD and IPF, and how it may be related to different clinical outcomes.
In COPD, the role of inflammation is consolidated; alveolar macrophages (AM), which are one of the main actors of innate immune response, were firstly recognized to play a key role in the pathogenesis of the disease, by releasing protease that damage lung parenchyma. In our studies, we investigated how AM may be involved in the development of COPD with alternative mechanisms; for example, we analyzed AM polarization, classic (M1) and alternative (M2), in lung tissue and how it may be influenced by smoking and disease severity. The model of COPD as a disease caused only by an antiprotease-protease imbalance has been overtaken; indeed, not all subjects with α1-Antitrypsin (AAT) deficiency (AATD) develop disease, meaning that other immune regulatory factors are involved. In fact, we investigated α1AT polymerization in AM as a pro-inflammatory trigger, due to its abnormal accumulation in AM endoplasmatic reticulum. Moreover, we performed a genome wide analysis in siblings with AATD, with extreme phenotypes of the disease (emphysema/no emphysema), searching for genes variants that may modulate or promote inflammatory response, possibly explain these opposite manifestations.
Since the study of biomarkers is becoming of great interest in the field, we focused our research on adaptive immune cells in the blood, examining blood eosinophils (BE) and lymphocytes (BL), to investigate whether they can be predictor of clinical outcomes, and if they reflect what is happening in the lung. In addition, we have started to unravel the possible role of the peripheral BL in the development or prevention of cancer. Then we moved from peripheral blood to the lung tissue, examining how lymphocyte and eosinophil counts in the lung may change after the introduction of an anti-inflammatory treatment with Roflumilast, adding some clues on its mechanisms of action. Indeed, the study of lung infiltrate is mandatory to better understand the pathogenesis of the disease, and we are currently developing new techniques to deeply analyze the immune cells in COPD lung, and the presence of markers of immunomodulation.
In IPF, the role of inflammation is more debated than COPD. Our idea that an inflammatory reaction could be an important part of IPF has lead us to investigate the possible role of innate and adaptive immune response in the pathogenesis of the disease, not only in explanted lungs of end-stage IPF, but also in the surgical lung biopsies of patients with mild disease. The pathological evidences we found were then correlated to clinical outcomes, as disease progression, to study if they may account for the variability in lung function decline. Moreover, we also explored whether different lung tissue inflammatory profiles may impact on the response to Pirfenidone treatment, which exerts also an anti-inflammatory effect. Finally, we investigated HRCT as a possible non-invasive predictor of disease behavior and treatment response in IPF.
The results of the studies we have conducted so far, highlights how inflammatory response, and especially the immune regulation, is pivotal in COPD and IPF, adding novel findings to previous knowledge in the areas of innate and adaptive inflammation, and putting the basis for future research in these smoking-induced diseases.
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Jones, Rhys Thomas. "Clinical approach to gastro-oesophageal reflux in idiopathic pulmonary fibrosis." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3308.
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Idiopathic pulmonary fibrosis is a progressive condition with limited treatment options and median survival of 3-5 years. Gastro-oesophageal reflux (GOR) has been described in up to 90% of patients. Pulmonary aspiration has been suggested to contribute to IPF, with calls for aggressive antireflux therapy. Whilst medical therapy can usually control acid reflux, surgery may be required to control non-acid refluxate, which may also be harmful if aspirated into the lung. The risks of surgery in the IPF population are significant. There is no validated technique with which to measure aspiration in this group and furthermore, patient attitudes towards the treatment of reflux and aspiration in IPF are unknown. As a result, the population that might benefit from antireflux therapy has yet to be defined. The current study comprised two main aims. The first was to characterise reflux and aspiration in an IPF cohort. The second was to evaluate patient attitudes towards the burden of IPF disease as compared to the burden of antireflux therapy. Methods Symptoms of reflux and lung health were assessed using a panel of structured questionnaires. Oesophageal function and gastro-oesophageal reflux were objectively assessed using manometry and pH-impedance monitoring. A standardised bronchoscopy and bronchoalveolar lavage, with biochemical and cytological analysis, was used to assess pulmonary aspiration. A separate group of individuals with IPF participated in an interview study. Respondents’ own health was evaluated using a visual analogue scale, the EuroQOL-5D -3L survey and a standard gamble utility analysis. Vignettes were constructed to describe mild- and moderate-severity IPF health states and adverse outcomes from medical and surgical antireflux therapy. Patient attitudes towards these four health states were assessed with a ranking exercise and a series of standard gambles. Results pH-impedance monitoring demonstrated supranormal levels of gastro-oesophageal reflux in 22 of 36 study subjects (61%). Eleven subjects had pre-existing evidence of gastro- ii oesophageal reflux and questionnaire assessment suggested GORD in 29% of subjects. Oesophageal manometry identified abnormal oesophageal function in 56%. Supranormal levels of pepsin were detected in bronchoalveolar lavage fluid in 16 subjects. The combination of pepsin quantification and oesophageal monitoring identified a subgroup of subjects with evidence of reflux and aspiration, but there was no correlation between levels of reflux and pepsin concentrations. Cytological staining results correlated poorly with gastro-oesophageal reflux. After formal multidisciplinary review, two patients who participated in the current study have undergone fundoplication. Both have enjoyed a stable disease course since surgery. In the interview study, respondents recorded mean utilities of 0.611 to 0.798 for their own health. Amongst 59 respondents, 38 regarded both IPF health states as preferable to the outcomes of either antireflux therapy outcome; the remainder disagreed. An adverse outcome from antireflux surgery was generally regarded as the worst of the health states. Discussion Oesophageal physiology and BAL fluid analysis may be combined to investigate reflux and aspiration in IPF. The current data suggest that reflux is common and frequently asymptomatic. Aspiration may only be significant in the minority of patients. Oesophageal dysmotility, a relative contra-indication to fundoplication, was evident in the majority of subjects. This is the first report of health state utilities for IPF and demonstrates a disease burden comparable to advanced lung cancer. Opinion was divided as to the relative burden associated with IPF disease and the potential outcomes of antireflux therapy. In conclusion, it remains difficult to identify the IPF patients for whom antireflux surgery might be most beneficial. For a proportion, the risks of such treatment will be prohibitive. The complexity of surgical decisions in this group suggests a requirement for a standard of care that includes a multidisciplinary team, informed by objective aerodigestive physiology and imaging.
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Molyneaux, Philip. "Host genetics and the respiratory microbiome in idiopathic pulmonary fibrosis." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/44524.
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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause that leads to respiratory failure and death within five years of diagnosis. It is thought to arise in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. The exact triggers, which initiate the fibrotic process, remain unknown. Overt respiratory infection and immunosuppression carry a high mortality, while polymorphisms in genes related to epithelial integrity and host defence predispose to IPF. There has however, been no systematic search for potential infective sources of alveolar injury in IPF. Methods: Patients diagnosed with IPF were prospectively enrolled, together with matched controls, and followed up over a two-year period. Subjects underwent bronchoalveolar lavage (BAL) at recruitment and during any exacerbations allowing quantification of bacterial load and identification of communities by 16S rRNA qPCR and pyrosequencing (Roche 454). Longitudinal peripheral whole blood gene expression profiles were generated (Affymetrix 1.1ST Arrays) and MUC5B SNP genotyping performed. Results: IPF patients have double the burden of bacteria in BAL compared to controls. Baseline bacterial burden predicted the rate of decline in lung volume, risk of death and associated independently with the rs35705950 polymorphism of the MUC5B gene. Haemophilus, Streptococcus, Neisseria and Veillonella spp. were more abundant in cases than controls. During an exacerbation of IPF there is an increase in BAL bacterial burden and changes in the microbiome from baseline. Peripheral whole blood gene expression profiling has given potential mechanistic insights in to the pathogenesis of IPF. A total of 1,358 transcript clusters, differentially expressed between cases and controls, were identified. Apoptosis, oxidative stress, angiogenesis, cellular inflammation and antimicrobial processes were all implicated. Novel potential interactions with well established putative fibrotic pathways were identified and for the first time longitudinal expression changes in IPF subjects were demonstrated. Conclusions: IPF is characterized by an increased bacterial burden in BAL that predicts decline in lung function and death. Bacterial burden and the microbiota both change during an exacerbation, despite current guidelines dictating they are non-infective events. The association demonstrated between bacterial load and MUC5B genotype suggests there may be a direct relationship between host immunity and the respiratory microbiome. IPF patients have a characteristic peripheral blood transcriptome. Longitudinal expression and WCGNA analysis not only identified genes associated with IPF and survival but also confirmed previously suggested potential prognostic biomarkers including Lymphocyte-specific protein tyrosine kinase (LCK).
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Tomioka, Hiromi. "The clinical course and new treatment of idiopathic pulmonary fibrosis." Kyoto University, 2008. http://hdl.handle.net/2433/124326.
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Sokai, Akihiko. "Matrix metalloproteinase-10: a novel biomarker for idiopathic pulmonary fibrosis." Kyoto University, 2016. http://hdl.handle.net/2433/215399.
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Jaffar, Jade. "The extracellular matrix protein fibulin-1 in idiopathic pulmonary fibrosis." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12800.
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One of the most pressing issues in the clinical management of patients with idiopathic pulmonary fibrosis (IPF) is how a clinician can respond when asked “how long do I have?” IPF has a varied clinical course and the only available treatments, aside from lung transplantation, are corticosteroids and immunosuppressants. The side effects of both corticosteroids and immunosuppressants may actually outweigh the benefits for use in IPF. Biomarkers of disease progression are often unable to predict acute lung function decline. This is possibly because the underlying mechanisms driving the disease are poorly understood and little attention has been paid to how intrinsic differences in resident lung fibroblasts may be contributing to this disease. In this thesis, extracellular matrix (ECM) molecules that are both found in the blood and released by resident lung fibroblasts were investigated for their utility as biomarkers of disease progression in IPF. The primary focus was on the ECM protein fibulin-1, an essential constituent of elastic fibres, which has not previously been studied in the context of interstitial lung disease. This thesis investigated the relationship between fibulin-1, and disease severity in patients with and without pulmonary fibrosis. In addition, the utility of fibulin-1 as a biomarker of disease progression was compared against other previously described components of the ECM, namely periostin, tenascin-C and fibronectin, in the same patients. Lastly, the effect of the profibrotic cytokine transforming growth factor-beta-1 (TGFβ1) on fibulin-1 levels in resident lung fibroblasts from patients with and without IPF was interrogated.
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Ngoubo, Ngangue-Courcot Elisabeth. "Implication des microARN dans le développement des maladies pulmonaires à composante environnementale : exemple de le fibrose pulmonaire idiopathique." Thesis, Lille 2, 2012. http://www.theses.fr/2012LIL2S051/document.
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Les microARN sont des petits ARN non codants d’une vingtaine de nucléotides qui ont pour fonction de réguler l’expression des gènes en se fixant sur l’extrémité 3’UTR d’ARNm cibles, permettant ainsi leur dégradation ou l’arrêt de leur traduction en protéines. A ce jour, de nombreuses études ont montré l’implication des microARN dans divers processus physiologiques ou pathologiques ; leur rôle dans la réponse de l’organisme aux substances toxiques environnementales commence à être évoqué.La FPI appartient au groupe des pneumopthies interstitielles diffuses idiopathique dont elle est la forme la plus fréquente. Elle se caractérise par la présence de foyers de prolifération de fibroblastes/myofibroblastes responsables d’une production excessive de matrice extracellulaire, une destruction progressive et irréversible de l’architecture pulmonaire entrainant la perte de la fonction respiratoire. L’agression répétée de l’épithélium respiratoire par des composés chimiques environnementaux (ou xénobiotiques) est fortement suspectée dans le déclenchement de la FPI.Le premier objectif de mes travaux de recherche a été d’identifier des microARN susceptibles d’intervenir dans la pathogenèse de la fibrose pulmonaire idiopathique (FPI) et de préciser la (les) fonction(s) de ces microARN d’intérêt. Pour atteindre cet objectif, nous avons étudié deux microARN, le miR-199a-5p et le miR-214-3p qui présentaient la particularité d’être significativement surexprimés dans les poumons de souris souffrant de fibrose pulmonaire. L’analyse systématique des profils d’expression des gènes de fibroblastes surexprimant le miR-199a-5p et le miR-214-3p nous a permis d’identifier un grand nombre de gènes qui étaient significativement modulés par ces deux microARN. Nous avons pu établir l’implication respective du miR-199a-5p et du miR-214-3p dans la régulation de la voie profibrotique TGFβ et dans l’apoptose des fibroblastes pulmonaires médiée par le Fas-ligand. L’ensemble de nos résultats nous permet de suggérer l’utilisation de molécules ciblées contre ces 2 microARN dans le traitement de la FPI.Le second objectif de mes travaux de recherche a été d’identifier le modèle cellulaire in vitro le plus proche du tissu pulmonaire afin d’étudier l’impact des composés toxiques environnementaux sur la pathogenèse des maladies respiratoires et, en particulier, de la FPI. Pour cela, nous avons comparé les profils d’expression génique de l’ensemble des protéines impliquées dans le métabolisme et l’éliminations des xénobiotiques, de 10 lignées cellulaires et de 4 cultures primaires de cellules épithéliales bronchiques humaines, à ceux précédemment observés par notre équipe dans les tissus broncho-pulmonaires humains. L’exposition du modèle cellulaire le plus pertinent à des polluants atmosphériques permettra d’identifier les microARN associés à la toxicité pulmonaire de ces composés chimiques et de vérifier si ces microARN régulent des voies de signalisations communes à celles impliquées dans la pathogenèse de la FPIMicroRNAs are small non-coding RNAs with about 20 nucleotides that regulate gene expression by binding to the 3' UTR end of target mRNAs, thus allowing their degradation or stopping their translation into proteins. To date, many studies have shown the involvement of microRNAs in various physiological or pathological processes; their role in the body's response to environmental toxic substances is beginning to be mentioned. It is characterized by the presence of fibroblast/myofibroblast proliferation foci responsible for excessive extracellular matrix production, progressive and irreversible destruction of lung architecture leading to loss of respiratory function. The repeated aggression of the respiratory epithelium by environmental (or xenobiotic) chemicals is strongly suspected in the initiation of IVF. The first objective of my research was to identify microRNAs that may be involved in the pathogenesis of idiopathic pulmonary fibrosis (IVF) and to specify the function(s) of these microRNAs of interest. To achieve this objective, we studied two microRNAs, miR-199a-5p and miR-214-3p, which had the particularity of being significantly overexpressed in the lungs of mice with pulmonary fibrosis. Systematic analysis of the expression profiles of fibroblast genes overexpressing miR-199a-5p and miR-214-3p allowed us to identify a large number of genes that were significantly modulated by these two microRNAs. We were able to establish the respective involvement of miR-199a-5p and miR-214-3p in the regulation of the profibrotic pathway TGFβ and in Fas-ligand mediated apoptosis of pulmonary fibroblasts. The second objective of my research was to identify the in vitro cellular model closest to lung tissue in order to study the impact of environmental toxic compounds on the pathogenesis of respiratory diseases and, in particular, of IVF. To do this, we compared the gene expression profiles of all proteins involved in the metabolism and elimination of xenobiotics, 10 cell lines and 4 primary cultures of human bronchial epithelial cells, with those previously observed by our team in human bronchopulmonary tissues. Exposure of the most relevant cellular model to air pollutants will identify the microRNAs associated with the pulmonary toxicity of these chemical compounds and verify whether these microRNAs regulate signaling pathways common to those involved in the pathogenesis of IVF
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Boutanquoi, Pierre-Marie. "Traitement de la fibrose pulmonaire idiopathique : Rôle de TRIM33 et de l’inhibition d’HSPB5." Electronic Thesis or Diss., Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCI016.
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La fibrose pulmonaire idiopathique (FPI) est une maladie dévastatrice caractérisée par l’accumulation de matrice extracellulaire dans les poumons. Le transforming-growth-factor (TGF)-β1 est une cytokine pro-fibrosante qui active la voie des Smads. Nous avons déjà montré que la protéine de choc thermique HSPB5 a un rôle activateur sur cette voie dans la fibrogenèse. TRIpartite Motif-containing 33 (TRIM33) est un régulateur négatif de la voie TGF-β1/Smads mais son rôle dans la fibrogenèse est inconnu. Nous avons étudié, le rôle de TRIM33 dans la FPI dans des modèles in vivo et ex-vivo, ainsi que le potentiel thérapeutique d’inhibiteurs chimiques d’HSPB5 dans des modèles de fibrose pulmonaire.Nous avons montré que TRIM33 est surexprimé dans les foyers fibroblastiques (myofibroblastes) ainsi que dans les macrophages alvéolaires de patients FPI. L’inhibition de cette protéine aggrave la différenciation mésenchymateuse, in vitro et in vivo, mais augmente également la sécrétion de TGF-β1 par les macrophages. En parallèle, nous avons mis en évidence l’efficacité de plusieurs inhibiteurs spécifiques de HSPB5, dans des modèles cellulaires de fibrose. Ces inhibiteurs ont été capables de diminuer l’augmentation des marqueurs de la différenciation mésanchymateuse induite dans le TGF-β1. Un de ces inhibiteurs s’est déjà révélé efficace pour traiter la fibrose pulmonaire induite par la bléomycine chez la souris.En conclusion, ce travail de thèse a permis de mettre en évidence le rôle de TRIM33 dans le développement de la FPI ainsi que l’efficacité d'inhibiteurs spécifiques de HSPB5 qui permettront peut-être un jour le traitement de la fibrose pulmonaire idiopathiqueIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix (ECM) accumulation in the lungs. Transforming-growth-factor (TGF)-β1 is a key profibrotic growth factor involving Smads signaling pathway. We have already shown that the heat shock protein HSPB5 has a positive role on Smads pathway activation in lung fibrogenic processes. TRIpartite Motif-containing 33 (TRIM33) has previously been reported to exert a negative control on TGF-β/Smads signaling but its role in pulmonary fibrogenesis remains unknown.We aimed to study the role of TRIM33 in IPF using ex vivo and in vivo models and to characterize the therapeutic potential of specific HSPB5 inhibitors.TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients. Its inhibition led to increased TGF-β1 downstream gene expression. In addition TRIM33 depletion worsened TGF-β1 secretion by the macrophages. Moreover, we demonstrated that several specific HSPB5 inhibitors were able to downregulate the up- regulation of mesenchymal differenciation induced by TGF-β1 in in vitro models. Moreover, one of these inhibitors proved to be effective in BLM-induced fibrosis models.In conclusion, this work has allowed to demonstrate the importance of TRIM33 in the development of IPF as well as to characterize efficient HSPB5 specific inhibitors that may be used one day as treatment for IPF
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Roach, Katy Morgan. "The role of the K⁺ channel KCa3.1 in idiopathic pulmonary fibrosis." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/27825.
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Idiopathic pulmonary fibrosis (IPF) is a common disease with a median survival of only 3 years. There is no effective treatment. IPF is characterized by myofibroblast accumulation and progressive lung scarring. The Ca²⁺-activated K⁺ channel KCa3.1 modulates the activity of several structural and inflammatory cells which play important roles in model diseases characterized by tissue remodelling and fibrosis. We hypothesise that KCa3.1-dependent cell processes are a common denominator in IPF. KCa3.1 expression and function were examined in human myofibroblasts derived from IPF and non-fibrotic (NFC) donors. Myofibroblasts grown in vitro were characterised by western blot, immunofluorescence, RT-PCR and patch clamp electrophysiology to determine KCa3.1 channel expression. Wound healing, collagen secretion and contraction assays were performed using the pro-fibrotic mediators TGFβ1 and bFGF and two specific KCa3.1 blockers (TRAM-34, ICA-17043 [Senicapoc]). Both NFC and IPF myofibroblasts expressed KCa3.1 channel mRNA and protein. Using the KCa3.1 channel opener 1-EBIO, KCa3.1 ion currents were elicited in 59% of NFC and 77% of IPF myofibroblasts tested (P=0.0411). These currents were blocked by TRAM-34 (200 nM). The 1-EBIO-induced currents were significantly larger in IPF cells compared to NFC cells (P=0.0078). TGFβ1 and bFGF increased KCa3.1 channel expression. TRAM-34 and ICA-17043 dose-dependently attenuated wound healing, TGFβ1-dependent collagen secretion and bFGF- and TGFβ1-dependent contraction. We show for the first time that human lung myofibroblasts express the KCa3.1 K⁺ channel. KCa3.1 channel block attenuates pro-fibrotic myofibroblast function. These findings raise the possibility that blocking the KCa3.1 channel will inhibit pathological myofibroblast function in IPF, and thus offer a novel approach to IPF therapy.
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Crooks, Michael George. "A study of platelets and the endothelium in idiopathic pulmonary fibrosis." Thesis, University of Hull, 2012. http://hydra.hull.ac.uk/resources/hull:6872.
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Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease associated with significant morbidity and early mortality. Despite this, the pathogenesis remains poorly understood and there is no effective disease modifying treatment. Epidemiological studies demonstrate an association between IPF and vascular disease. Platelets and the endothelium play an important role in maintaining vascular integrity, patency and function. In addition to their role in haemostasis, platelets have significant inflammatory and pro-fibrotic potential. Platelets and the lung have a close relationship in physiology and in disease however the role of platelets in IPF has not previously been investigated. In this thesis we investigate the link between IPF and vascular disease and consider a potential pathogenic role of platelets in IPF. We do this through the following series of experiments: (1) investigation of the platelet endothelial cell adhesion molecule-1 single nucleotide polymorphisms in IPF and controls; (2) assessment of markers of platelet activation in IPF and controls; (3) investigation of the effect of IPF plasma on control platelets; (4) assessment of platelet function by measurement of platelet-endothelial cell adhesion; and (5) evaluation of plasma markers of endothelial activation and fibrinolysis in IPF. We demonstrate that IPF patients exhibit increased platelet reactivity and that this can be reproduced in control platelets following incubation in IPF plasma suggesting that a plasma factor is responsible for this phenomenon. In addition, we show that the increased platelet reactivity in IPF is associated with an increased propensity to adhere to vascular endothelium confirming abnormal platelet function in IPF patients and suggesting a potential pathogenic mechanism. We do not demonstrate any difference in plasma levels of endothelial activation markers or fibrinolysis between IPF patients and controls. Similarly, we find no clinically significant difference in the prevalence of the PECAM-1 polymorphisms in IPF and controls.
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Huang, Yong, Shwu-Fan Ma, Rekha Vij, Justin M. Oldham, Jose Herazo-Maya, Steven M. Broderick, Mary E. Strek, et al. "A functional genomic model for predicting prognosis in idiopathic pulmonary fibrosis." BioMed Central Ltd, 2015. http://hdl.handle.net/10150/610303.
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BACKGROUND: The course of disease for patients with idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. Prognostic models rely on demographic and clinical characteristics and are not reproducible. Integrating data from genomic analyses may identify novel prognostic models and provide mechanistic insights into IPF. METHODS: Total RNA of peripheral blood mononuclear cells was subjected to microarray profiling in a training (45 IPF individuals) and two independent validation cohorts (21 IPF/10 controls, and 75 IPF individuals, respectively). To identify a gene set predictive of IPF prognosis, we incorporated genomic, clinical, and outcome data from the training cohort. Predictor genes were selected if all the following criteria were met: 1) Present in a gene co-expression module from Weighted Gene Co-expression Network Analysis (WGCNA) that correlated with pulmonary function (p < 0.05); 2) Differentially expressed between observed "good" vs. "poor" prognosis with fold change (FC) >1.5 and false discovery rate (FDR) < 2 %; and 3) Predictive of mortality (p < 0.05) in univariate Cox regression analysis. "Survival risk group prediction" was adopted to construct a functional genomic model that used the IPF prognostic predictor gene set to derive a prognostic index (PI) for each patient into either high or low risk for survival outcomes. Prediction accuracy was assessed with a repeated 10-fold cross-validation algorithm and independently assessed in two validation cohorts through multivariate Cox regression survival analysis. RESULTS: A set of 118 IPF prognostic predictor genes was used to derive the functional genomic model and PI. In the training cohort, high-risk IPF patients predicted by PI had significantly shorter survival compared to those labeled as low-risk patients (log rank p < 0.001). The prediction accuracy was further validated in two independent cohorts (log rank p < 0.001 and 0.002). Functional pathway analysis revealed that the canonical pathways enriched with the IPF prognostic predictor gene set were involved in T-cell biology, including iCOS, T-cell receptor, and CD28 signaling. CONCLUSIONS: Using supervised and unsupervised analyses, we identified a set of IPF prognostic predictor genes and derived a functional genomic model that predicted high and low-risk IPF patients with high accuracy. This genomic model may complement current prognostic tools to deliver more personalized care for IPF patients.
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Schickel, Maureen Erin. "Biomechanics of Idiopathic Pulmonary Fibrosis and Inferior Vena Cava Filter Perforation." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406048985.
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Fontoura, Fabrício Farias da. "Impacto de um programa de reabilitação pulmonar sobre a qualidade de vida relacionada à saúde e a capacidade funcional em indivíduos portadores de fibrose pulmonar idiopática." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/142897.
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Introdução: A fibrose pulmonar idiopática (FPI) é uma grave doença pulmonar crônica com sintomas de dispneia progressiva, resultando na diminuição da capacidade de exercício, impactando negativamente na qualidade de vida relacionada à saúde (QVRS). A reabilitação pulmonar (RP) melhora a capacidade funcional (CF) com redução dos sintomas, porém na FPI avançada seus efeitos e magnitudes são pouco conhecidos. Objetivo: Avaliar o impacto da RP sobre a QVRS e a CF em pacientes portadores de FPI. Métodos: Estudo de coorte retrospectiva em que foram revisados dados de 56 prontuários de pacientes em lista de transplante de pulmão com diagnóstico de FPI de acordo com o consenso da American Toracic Society 2011, submetidos a 12 semanas (36 sessões) de RP ambulatorial entre o período de janeiro de 2008 a outubro de 2012. Foram avaliadas a CF e a QVRS através do teste de caminhada de seis minutos (TC6) e do questionário 36-item short-form survey, SF36, respectivamente, antes e imediatamente após a RP. Resultados: Vinte e sete pacientes foram incluídos no estudo, 16 (61%) gênero masculino com idade média de 53 ±13 anos. Dezoito pacientes (68%) tinham diagnóstico histológico por biópsia pulmonar com padrão de pneumonia intersticial usual (PIU), com tempo médio de diagnóstico de 3 ±1,7 anos. Quanto à classificação da dispneia pela escala modified Medical Research Council (mMRC) basal, 59% dos pacientes foram classificados entre 3-4. Houve aumento significativo na distância percorrida de 393 ±88 metros para 453 ±90 metros (p<0,001). As medianas de dispneia sofreram diminuição significativa (p=0,01) na escala do mMRC de 2 (IC95%: 1-4) para 1 (IC95%: 1-4) e de 5 (Mín/Máx:1-10) para 3 (Mín/Máx:0-10) no BORG de dispneia no final do TC6. Apesar de caminharem maiores distâncias, a fadiga em membros inferiores foi menor com uma mediana de 2 (Mín/Máx:0-10) para 1 (Mín/Máx:0-9) (p=0,02). Houve aumento em 5 dos 8 domínios, porém somente a capacidade funcional foi significativa de 26 (IC95%: 19-33) para 37 (IC95%: 27-48) (p<0,05); os demais domínios não tiveram significância estatística. Conclusão: Observaram-se nestes pacientes aumentos da CF, com diminuição dos sintomas dispneia e fadiga; o que não se refletiu em melhora clínica na QVRS em portadores de FPI em lista de transplante de pulmão após um programa de RP.Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with severe symptoms of progressive dyspnea, resulting in decreased exercise capacity, negatively impacting the health-related quality of life (HRQL). Pulmonary rehabilitation (PR) improves functional capacity (FC) with reduction in symptoms, but in advanced IPF, its effects and magnitudes are unknown. Objective: To evaluate the impact of PR and in HRQL and in FC of patients with IPF. Methods: Coorte study with a retrospective review of data from 56 medical records of patients on lung transplant list diagnosed with IPF according to the American Toracic Society 2011 consensus, submitted to 12 weeks (36 sessions) of outpatient RP between January 2008 and October 2012. The FC and the HRQL were assessed through a six-minute walk test (6MWT) and the 36-item short-form survey (SF36) respectively before and immediately after PR. Results: Twenty-seven patients were included in the study, 16 (61%) male with a mean age of 53 ± 13 years. Eighteen patients (68%) had histologic diagnosis by lung biopsy compatible with usual interstitial pneumonia (UIP), with median time from diagnosis of 3 ± 1.7 years. Regarding the classification of the dyspnea in the modified Medical Research Council (mMRC) scale, 59% of patients were classified between 3-4. There was a significant increase in the distance covered from 393 ± 88 meters to 453 ± 90 meters (p <0.001). The baseline medians of dyspnea had a significant decrease (p = 0.01) in the mMRC scale from 2 (CI 95%: 1-4) to 1 (CI 95%: 1-4) and the median decreased from 5 (Min/Max: 1-10) to 3 (Min/Max :0-10) in the Borg dyspnea index at the end of the 6MWT. Although the patients walked greater distances, they had less fatigue in the legs, with a median decrease from 2 (Min/Max: 0-10) to 1 (Min/Max: 0-9) (p = 0.02). There was an increase in 5 of the 8 domains, but only the functional capacity was significant: from 26 (CI95%: 19-33) to 37 (CI95%: 27-48) (p <0.05), while the remaining areas were not statistically significant. Conclusion: We observed increases of FC in these patients, with decreased symptoms of dyspnea and fatigue; which were not reflected in clinical improvement in HRQL of patients with IPF on lung transplant list after a PR program.
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Henaoui, Imène Sarah. "MiR-199a-5p, un « fibromiR » amplificateur de la voie du TGF-beta dans la fibrose pulmonaire idiopathique." Electronic Thesis or Diss., Nice, 2013. http://www.theses.fr/2013NICE4136.
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La Fibrose Pulmonaire idiopathique (FPI) est une maladie fibroproliférative pour laquelle il n’existe aucun traitement efficace. Les mécanismes à l’origine de cette pathologie sont méconnus et impliquent plusieurs types cellulaires et facteurs de croissance, comme le TGF-β responsable de la différenciation de fibroblastes en myofibroblastes. Pour mieux comprendre ces mécanismes physiopathologiques, nous nous sommes intéressés à l’implication des miARN dans ce processus. Une analyse par puces à ADN de l’ensemble des miARN modulés dans des échantillons pulmonaires de souris, résistantes ou sensibles à la fibrose pulmonaire induite par la bléomycine, nous a permis d’identifier miR-199a-5p comme le meilleur candidat associé à la fibrose pulmonaire mais aussi fibrose rénale et hépatique. J’ai ensuite démontré que l’expression de miR-199a-5p était induite par le TGF-β in vitro, et que sa surexpression ectopique induisait la différenciation des fibroblastes. Une combinaison d’approche in silico et expérimentale, m’a permis d’identifier la Cavéoline-1 (CAV-1) comme cible de ce miARN. La CAV-1 est impliquée dans la dégradation du récepteur TGF-β. Ainsi, l’inhibition de CAV-1 par miR-199a-5p constitue une boucle de rétrocontrôle positif exacerbant la voie TGF-β. De manière intéressante, l’inhibition de miR-199a-5p in vitro régule la différenciation, la prolifération et la migration des fibroblastes pulmonaires par le TGF-β. Par ailleurs, nos résultats précliniques indiquent que l’inhibition de ce miARN diminue les marqueurs de fibrose, permettant d’envisager le développement de nouvelles approches thérapeutiques dans le traitement de la FPI et d’autres maladies fibroproliférativesIdiopathic Pulmonary Fibrosis (IPF) is a fibroproliferative disease with poor prognosis and for which no effective treatment exists. The mechanisms of this disease remain poorly understood and involve numerous cell types and growth factors such as TGF-β, which leads to the activation of lung fibroblasts into myofibroblasts; the key cell type driving the fibrogenic process. In this context, we focused the involvement of miRNAs in fibrosis process. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to lung fibrosis after bleomycin exposure. We identified miR- 199a-5p as the best candidate associated with lung fibrosis but also kidney and liver fibrosis. I observed that miR-199a-5p expression was induced upon TGF-β exposure, and that its ectopic expression was sufficient to promote the pathogenic activation of pulmonary fibroblasts. Using combination of targets miRNA prediction tools and a transcriptomic approach we identified the Caveolin-1 (CAV-1), a critical mediator of pulmonary fibrosis, as a specific target of miR-199a-5p. Thus, we shown that miR-199a-5p is a key effector of TGF-β signaling in lung fibroblasts by regulating CAV1. Interestingly, inhibition of miR-199a-5p in vitro prevents the differentiation, proliferation and migration of fibroblasts after TGF-β stimulation. Finally, our preclinical results indicate that inhibition of this miRNA decreases fibrosis markers. Thus, miR-199a-5p behaves as a major regulator of tissue fibrosis with therapeutic potency for the treatment of IPF and fibroproliferative diseases
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Kanda, N. "Fibroblast spheroids : a useful assay for drug screening in idiopathic pulmonary fibrosis?" Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1463756/.
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Introduction: Idiopathic pulmonary fibrosis (IPF) is characterised by excessive deposition of extracellular matrix proteins and destruction of the lung architecture. The aetiology of this disorder is unknown and few effective therapies are available. Several models have been established to identify key pathological cells and mediators that may be important in IPF, however these models lack the classical histopathological features seen in IPF, such as fibrotic foci. The aim of this project was to develop a novel 3-D in vitro assay system which more closely mimics a fibrotic focus, for pre-clinical drug evaluation. Methods: Primary human lung fibroblasts were isolated as outgrowths from small (<1 mm3) lung explants (non-IPF and IPF patients). Non-IPF (n = 10) and IPF (n = 10) fibroblasts were cultured in non- adherent 96-well plates to generate fibroblastic spheroids. Spheroid formation and phenotypic features were characterised using time-lapse videomicroscopy, histological analysis, (including TUNEL assay) and, electron microscopy. RNA was extracted from the spheroids and microarray analysis and qRT-PCR were used to analyse mRNA levels. Total collagen was measured using HPLC analysis of hydroxyproline levels while active TGFβ within the spheroid homogenates and supernatants were measured using the transformed mink lung epithelial cell bioassay. A medium-throughput screen of potential anti-fibrotic compounds (using a focused GSK compound library known as the fibrosis toolbox) was also performed, using hydroxyproline levels as the endpoint measure. Results: Non-IPF and IPF fibroblasts were able to form non-proliferating spheroids within 24 hours of incubation, with clear organisation and orientation of cells within the spheroid. IPF spheroids had a myofibroblastic phenotype with increase expression of αSMA. TUNEL assay identified increased numbers of apoptotic cells in non-IPF spheroids in comparison to IPF spheroids, which may be due, in part, to autocrine/paracrine COX1-mediated PGE2 generation. The mink lung cell assay demonstrated that non-IPF and IPF spheroids spontaneously produced high levels of active TGFβ, which was partially dependent on β3 and β8 integrins. Antagonising TGFβ signalling did not however affect spheroid collagen production. Microarray data analysis illustrated a limited number of differentially expressed genes, with the majority involved in encoding proteins that play a key role in metabolic pathways. The fibrosis toolbox identified potential target molecules that impact on collagen biosynthesis including EP2/4 compounds, an integrin αv inhibitor, Smo antagonists, MCP-1 inhibitor, and mTORC 1/2 inhibitors. Conclusions: Fibrotic fibroblast spheroids mimic some of the key characteristics of fibroblasts in fibrotic foci of IPF lungs (i.e. increased collagen production, elevated levels of active TGFβ and resistance to apoptosis). In addition, microarray and medium-throughput screening identified several potential targets. Therefore, fibrotic fibroblast spheroids may represent a novel assay system for pre-clinical drug evaluation, and warrant further investigation.
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Wright, Rebecca. "cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/35925/.
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Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with no effective treatment. Myofibroblasts contribute to the pathology of IPF by secreting large amounts of extracellular matrix proteins such as alpha smooth muscle actin (α-SMA) and Collagen I (Col 1). Myofibroblasts have reduced Prostaglandin E2 (PGE2), a key anti-fibrotic mediator, due to diminished cyclooxygenase-2 (COX-2) expression. Primary fibroblasts isolated from lungs of IPF patients (F-IPF) expressed significantly less COX-2 in response to IL-1β and increased α-SMA and Col I compared with fibroblasts isolated from lungs of non-fibrotic patients (F-NL). COX-2 was gradually lost in F-NL treated with transforming growth factor-β (TGF-β1), a pro-fibrotic cytokine, whereas PGE2, and cAMP elevating agents increased IL-1β-induced COX-2 expression in F-IPF. Ras, a small G protein, has been shown to have a role in several fibrotic conditions. Farnesylthiosalicylic acid (FTS), a Ras inhibitor, increased IL-1β-induced COX-2 and prevented TGF-β1-induced reduction of COX-2. Previous studies suggest that COX-2 is epigenetically repressed. LBH589, a HDAC inhibitor, prevented TGF-β1-induced repressed COX-2 whereas BIX01294, a DNA lysine methyltransferase inhibitor, and RG108, a G9a histone methyltransferase inhibitor, both increased IL-1β-induced COX-2 in F-IPF. In conclusion, the gradual loss of PGE2/COX-2 anti-fibrotic mechanism during myofibroblast differentiation may contribute to the pathophysiology of pulmonary fibrosis and agents that increase cAMP levels, inhibit Ras or inhibit epigenetic repression of COX-2, may compensate for the lack of endogenous PGE2.
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Liu, Yi-Chia. "Understanding chronic inflammatory diseases in the human lung : the cystic fibrosis and idiopathic pulmonary fibrosis paradigms." Thesis, University of Nottingham, 2014. http://eprints.nottingham.ac.uk/27807/.
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The chronic infection of the cystic fibrosis (CF) lung with Pseudomonas aeruginosa strongly correlates with critical outcomes. Pseudomonas alkyl-quinolone signal (PQS) is a diffusible cell-density dependent signal controlling the production of virulence determinants. The PQS amount in the CF lung was proportionate to P. aeruginosa colonisation and PQS molecules have been demonstrated to inhibit pro-inflammatory signalling. However, how PQS influence the recognition of P. aeruginosa by the human lung is unknown. The contribution of PQS to the interaction of P. aeruginosa with human bronchial epithelial cells (HBECs) was characterised using a PQS-deficient mutant ΔpqsA in comparison with its isogenic wild type (WT). Although ΔpqsA appeared attenuated, the pathogenesis of WT and ΔpqsA upon infection of HBEC did not differ in bacterial growth, actin and junctional protein degradation, and pro-inflammatory activation. Despite PQS being highly secreted by a CF isolate LESB58, preliminary data showed that LESB58 was less cytotoxic than the laboratory WT. Our results suggest that PQS does not alter P. aeruginosa pathogenicity on HBECs. Idiopathic pulmonary fibrosis (IPF) is characterised with heterogeneous pathological patterns caused by scarring leading to irreversible destruction of lung architecture. Emerging evidence suggests that dysregulated immunological events could cause the failure of tissue-healing. Systemic immune responses of patients with IPF and age- and sex-matched healthy donors were determined by quantifying cytokines produced by peripheral blood mononuclear cells (PBMCs) upon an array of stimuli. The results showed that PBMCs in patients with IPF were less likely to produce IL-17A, IL-10 and IL-13 than healthy controls (OR 0.14-0.3, 95% CI 0.003-0.03). Patients with lower levels of cytokines had a four to six-fold increased risk of death (HR 4.31-6.13, 95% CI 0.0052-0.0176). This study contributes to a better understanding of the role of PQS in P. aeruginosa pathogenesis and identified cytokine production as a novel biomarker in IPF.
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Choi, Seojin. "Flaxseed oil and prevention of pulmonary fibrosis." Diss., Kansas State University, 2012. http://hdl.handle.net/2097/15106.
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Doctor of PhilosophyDepartment of Human Nutrition
Richard C. Baybutt
Weiqun George Wang
Although omega-3 fatty acids have been a hot issue in nutrition for years, there remains a paucity of research on the topic of omega-3 fatty acid and pulmonary fibrosis and the mechanism is still unclear. The purpose of this research is to investigate the preventive effects of flaxseed oil for bleomycin-induced pulmonary fibrosis in rats and to find the possible underlying mechanisms. There are two experiments demonstrated in this dissertation, one is with various doses of flaxseed oil in the diet (0, 2.5, 5, 7.5, 10, 12.5, and 15 % (w/w)), and the other is with different times of sacrificing animals after oropharyngeal bleomycin treatment (days 7 and 21). In the first study, three proteins including transforming growth factor-[beta] (TGF-[beta]), interleukin-1 (IL-1), and [alpha]-smooth muscle actin ([alpha]-SMA), commonly associated with fibrotic inflammation in the lung, were examined by Western blot and fatty acids composition of the diets and tissues were analyzed by gas chromatography (GC). Fifteen percent of flaxseed oil group significantly reduced septal and vascular thickness and fibrosis in the lung, and significant cardiac fibrosis in the heart. The amount of IL-1 and [alpha]-SMA decreased significantly as the amount of omega-3 fatty acids increased, whereas TGF-[beta] did not change significantly. The next study further reported the time-course effect and potential underlying mechanisms. Both interleukin-6 (IL-6), a protein associated with fibrotic inflammation in the lung, and renin, an enzyme related to renin-angiotensin system, were examined by Western blot. The time-dependent increase of IL-6 in response to bleomycin treatment was reversed by flaxseed oil diet. Although renin was not significantly different in the kidney, it suggested that the renin-angiotensin system may be involved locally. In addition, the profiles of fatty acids in both liver and kidney tissues as measured by lipidomics demonstrated a significant increase of omega-3: omega-6 ratio in the flaxseed oil-fed groups. Overall, these results indicated for the first time that the omega-3 fatty acids rich in flaxseed oil inhibited the formation of pulmonary fibrosis in a dose-dependent manner - however the moderate dose of flaxseed oil was most effective - via anti-inflammatory mechanisms, which appears associated with the modulated fatty acid composition in the tissues.
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Philp, Christopher J. "The potential therapeutic effect of manipulating the extracellular matrix in idiopathic pulmonary fibrosis." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/35802/.
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Background: Idiopathic Pulmonary Fibrosis (IPF) is a physiologically devastating disease. The debilitating nature and high mortality rates make this one of the most lethal conditions, usually associated with median time to mortality of around 3 years. Increased deposition of extracellular matrix (ECM) and fibroblast accumulation are hallmarks of idiopathic pulmonary fibrosis (IPF). We hypothesise that the ECM in IPF is structurally abnormal by virtue of aberrant cross linking and promotes fibroblast accumulation. This study examined the structure and biological activity of IPF derived ECM and how this related to the expression of ECM cross linking enzymes as well as how inhibiting Transglutaminase 2 affects active fibrosis in the murine Bleomycin model. Methods: Primary fibroblasts from 3 patients with IPF and 3 controls were isolated from biopsy samples and characterised by immunocytochemistry. ECM from these cells was deposited onto tissue culture plastic, cells removed using ammonium hydroxide and confirmed by electron microscopy (SEM). IPF and control cells were then grown on their own ECM or ECM derived from other cells. ECM was labelled with 3H-proline and digested with recombinant proteases and tritium liberation counted by scintillation as a measure of collagen proteolysis. A pilot study was carried out where C57BL/5J mice received a single intratracheal instillation of Bleomycin (2mg/kg) and administered cystamine dihydrochloride by intraperitoneal injection (IP), once a day for ten consecutive days at 40mg/kg or 100mg/kg, at 3 different time points. Results: IPF derived fibroblasts had more distinct organisation of fibrous matrix filaments on the cell surface and between adjacent cells by SEM. Both control and IPF lung fibroblasts expressed transcripts for lysyl oxidase (LOX), LOXL1, LOXL2, LOXL3, LOXL4 and transglutaminase (TG) 2. IPF derived matrix increased expression of LOXL3 and TG2 transcripts, LOXL3 protein and TGase activity. Other cross linking enzymes were unchanged. To assess if IPF matrix affected fibroblast accumulation, I measured fibroblast adhesion, proliferation by MTT and EDU assays, and apoptosis by cleaved caspase 3, cleaved PARP and TUNEL assay on the different matrices. IPF matrix enhanced proliferation over control matrix in response to PDGF-BB. To determine if this pro-proliferative effect was dependent upon aberrant cross-linking we generated ECM from normal and IPF fibroblasts treated with cystamine dihydrochloride (TG2 inhibitor) or β-amino-proprionitrile (LOX family inhibitor). The enhanced fibroblast proliferation seen on IPF matrix was reduced close to levels of normal matrix by each cross link inhibitor. There was no effect on apoptosis induced by either FAS ligand or staurosporine when cells were seeded onto IPF or control matrix suggesting IPF ECM does not protect seeded fibroblasts from apoptosis. Bleomycin showed a trend towards increasing total lung hydroxyproline at day 24, 34 and 44 post administration however this was not statistically significant. Administration of cystamine at 40mg/kg/day showed no effect on total lung hydroxyproline. At day 34 post Bleomycin, cystamine administration showed a trend towards decreasing total lung hydroxyproline however again this was not statistically significant. Conclusions: The data supports the hypothesis that IPF derived matrix is structurally and functionally different from normal matrix. This results in enhanced fibroblast proliferation, adhesion and increased cross linking activity by effects on gene transcription. Inhibition of matrix cross-linking reduced this enhanced fibroblast adhesion and proliferation. Administration of cystamine dihydrochloride via IP injection for ten consecutive days at 100mg/kg/day in the Bleomycin model showed a trend towards decreasing total lung hydroxyproline.
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Pereira, Paulo Rogério. "Efeitos do treinamento físico aeróbico na fibrose pulmonar." Universidade Nove de Julho, 2014. http://bibliotecadigital.uninove.br/handle/tede/1346.
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Background: Idiopathic pulmonary fibrosis (IPF) is characterized by decline of lung function, increased inflammation and fibrosis mainly in the pulmonary interstitium, with serotonin (5-HT) and Akt signaling presenting a role. Aerobic training (AT) reduces lung injury in different models of pulmonary diseases. However, the mechanisms underlying the effects of AT in a model of bleomycin-induced lung fibrosis is unknown. Thus, this study investigated the effects of AT in a model of bleomycin-induced pulmonary fibrosis, as well as the participation of 5HT/Akt signaling. Methods: Seventy-two C57Bl/6 male mice were distributed in Control (Co), Exercise (Ex), Fibrosis (Fi) and Fibrosis+Exercise (Fi+Ex) groups. Bleomycin (1.5UI/Kg) was administered on day 1 and treadmill AT began on day 14 during 4 weeks. Total and differential cells count in bronchoalveolar lavage (BAL), IL-1beta, IL-6, CXCL1/KC, IL-10, TNF-alpha and TGF-beta levels in BAL fluid, collagen content in the lung parenchyma, 5-HT levels in BAL fluid and in serum, and the expression of 5-HT2b receptor and Aktphosphorylation were evaluated. Results: AT reduced bleomycin-increased number of total cells (p<0.001), neutrophils (p<0.01), macrophages (p<0.01) and lymphocytes (p<0.05) in BAL. AT also reduced the levels of IL-1beta (p<0.01), IL-6 (p<0.05), CXCL1/KC (p<0.001), TNF-alpha (p<0.001) and TGF-beta (p<0.001), while increased the levels of IL-10 (p<0.001). Collagen fibers deposition was also reduced by AT (p<0.01). These findings were followed by AT-reduced bleomycin-increased 5-HT levels in BAL fluid (p<0.001) and in serum (p<0.05), as well as the expression of 5-HT2b receptor (p<0.01) and the Aktphosphorylation in lung tissue. Conclusions: We conclude that AT reduces lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis involving 5-HT/Akt signaling.
Introdução: A fibrose pulmonar idiopática (FPI) é uma doença devastadora com pobre prognóstico e nenhum tratamento efetivo disponível. Estudos recentes demonstram que a serotonina / 5-hidroxitriptamina (5-HT) desempenha um papel importante no processo de fibrose pulmonar. Entretanto, alguns estudos demonstram que o tratamento não farmacológico, como programas de reabilitação pulmonar para pacientes com FPI resulta em melhora da qualidade de vida e do manejo da doença, mas os efeitos sobre os pulmões e os possíveis mecanismos desses efeitos não são conhecidos. Objetivos: Portanto, o presente estudo investigou os efeitos do treinamento físico aeróbio na resposta pulmonar em um modelo de fibrose pulmonar induzida por bleomicina em camundongos, e os possíveis efeitos moduladores do exercício sobre os níveis de 5-HT. Materiais e métodos: Foram utilizados setenta e dois camundongos machos C57/Bl6, os quais foram distribuídos em Controle (Co), Exercício (Ex), Fibrose (Fi) e Fibrose + Exercício (Fi + Ex). Vinte e quatro horas após o último teste físico na esteira, a inflamação pulmonar foi avaliada através da avaliação do lavado broncoalveolar (contagem de células e medidas de citocinas: IL-1beta, IL-6, CXCL1/KC, IL-10, TNF-alfa, TGF-beta), e o remodelamento pulmonar através do acúmulo de fibras colágenas no parênquima pulmonar. Foram avaliados também os níveis de 5-HT no sobrenadante do lavado broncoalveolar e no soro. Além disso, a expressão do receptor para 5-HT (5-HT2B) também foi avaliado no tecido pulmonar. Por fim, a expressão da forma integral e fosforilada da Akt também foi avaliada no tecido pulmonar. Resultados: Os resultados demonstraram que o treinamento aeróbio reduziu o número de células totais (p<0.001), de neutrófilos (p<0.01), de macrófagos (p<0.01) e de linfócitos (p<0.05) no lavado broncoalveolar, assim como reduziu os níveis de IL-1beta (p<0.01), IL-6 (p<0.05), CXCL1/KC (p<0.001), TNF-alfa (p<0.001) e TGF-beta (p<0.001) no lavado broncoalveolar, enquanto aumentou os níveis da citocina anti-inflamatória IL-10 (p<0.001). O treinamento físico também reduziu a deposição de fibras de colágeno no parênquima pulmonar (p<0.001). Os níveis de 5-HT no sobrenadante do lavado broncoalveolar (p<0.001) e no soro (p<0.05) e a expressão do receptor 5HT2B (p<0.01) no tecido pulmonar demonstraram-se reduzidos no grupo submetido ao treinamento físico. A expressão de Akt na forma total não foi alterada pelo treinamento físico, enquanto que a forma fosforilada foi reduzida pelo treinamento físico (p<0.01). Conclusões: Os resultados do presente estudo demonstram claramente que o treinamento físico aeróbio é capaz de reduzir a inflamação e a fibrose pulmonar em um modelo experimental de fibrose pulmonar induzida pela bleomicina. Os resultados também demonstram que pelo menos em parte, esses efeitos benéficos do treinamento físico aeróbio pode ter sido mediado pelo aumento da liberação de IL-10, assim como pela redução da exacerbação dos níveis de serotonina, levando a uma redução da expressão do receptor de serotonina 5-HT2B, e também da redução da ativação da proteína Akt.
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Hames, Thomas. "Investigating the role of epithelial-mesenchymal crosstalk in the pathology of idiopathic pulmonary fibrosis." Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/33142.
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Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology, characterised by the progressive and irreversible scarring of parenchymal lung tissue that leads to respiratory failure and death. The disease is understood to be driven by an impaired and aberrant wound healing response, with an inappropriate reactivation of developmental signalling. The greatest risk factor for the disease is age, which is a process intimately associated with an increase in the burden of senescent cells. Such cells acquire a unique secretory phenotype and are known to have a significant impact on their local micro-environment. It was hypothesised that an alteration in epithelial-mesenchymal secretory communication, due to senescent-like changes in the fibroblast phenotype, may detrimentally contribute to lung homeostasis. An in vitro model of the lung airway was established in which primary human lung fibroblasts (HLFs) were co-cultured with human bronchial epithelial cells (HBECs). HBECs were cultured on a semi-permeable, transwell insert and co-cultured with either normal (NHLF), fibrotic (FHLF) or senescent fibroblasts. Over 72 hrs of co-culture, wound healing was assessed, via an epithelial scratch assay, and epithelial regeneration was measured, via trans-epithelial electrical resistance. Co-culture with NHLFs improves epithelial regeneration, however, FHLFs and senescent cells in co-culture show a diminished ability to promote epithelial regeneration and wound repair. The secretory repertoire of these cells contains elevated levels of IL-6, CXCL8, CXCL1 and GCSF (when assessed at both an RNA and protein level), factors strongly associated with the senescent phenotype. Targeting this secretome via treatment with the JAK 1/2 inhibitor Ruxolitinib attenuates these impairments and may point towards a new therapeutic strategy for the treatment of IPF.
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Farrokhi, Moshai Elika. "Rôle de la voie hedgehog dans la fibrose pulmonaire idiopathique." Thesis, Paris Est, 2013. http://www.theses.fr/2013PEST0107.
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La Fibrose Pulmonaire Idiopathique (FPI) est une maladie dévastatrice, d’étiologie inconnue, qui reste pour le moment incurable. Cette maladie est caractérisée par l’accumulation de fibroblastes et de protéines de la matrice extracellulaire dans les espaces aériens distaux aboutissant à une destruction alvéolaire et à une altération des propriétés mécaniques du poumon. La physiopathologie de la FPI est mal connue mais de nombreuses études suggèrent que la réactivation des voies impliquées dans le développement contribue à l’accumulation de la matrice extra-cellulaire et au comportement anormal des cellules épithéliales et des fibroblastes.La voie Hedgehog (HH) joue un rôle crucial dans le développement embryonnaire. Dans le développement pulmonaire fœtal, la voie HH est impliquée dans les interactions épithélium-fibroblaste et contrôle la prolifération et la différenciation du mésenchyme. La voie HH a été impliquée dans la fibrogénèse, notamment dans le foie et le rein.L’objectif de cette thèse a été de caractériser la voie HH dans la fibrose pulmonaire chez l’homme et dans un modèle de fibrose induite par la bléomycine chez la souris.Nous avons démontré que la voie HH est réactivée dans les tissus pulmonaires de patients atteints de FPI et dans le modèle de fibrose pulmonaire chez la souris. Nous avons montré que le TGF-β1 activait la voie HH dans les fibroblastes pulmonaires humains et que l’inhibition pharmacologique de la voie HH au niveau des facteurs GLI inhibait l’effet du TGF-β1 in vitro. Par contre, ces inhibiteurs ne protégent pas les cellules épithéliales alvéolaires de la transition épithélio-mésenchymateuse induite par le TGF-β1. In vivo, chez la souris, nous avons montré que le traitement par des inhibiteurs de Smoothened ne protégeait pas du développement de la fibrose tandis que le GANT61, un inhibiteur de l’interaction des GLI avec l’ADN, inhibait la fibrose.En conclusion, nos résultats démontrent l’implication de la voie HH dans la fibrose pulmonaire et ouvrent des perspectives thérapeutiques nouvellesIdiopathic Pulmonary Fibrosis (IPF ) is a devastating disease of unknown etiology, which no efficient treatment. This disease is characterized by the accumulation of fibroblasts and extracellular matrix proteins in the distal airways resulting to the destruction of alveoli and alteration of mechanical properties of the lung. The pathogenesis of IPF is not well known but many studies suggest that reactivation of pathways involved in the development, contributes to the accumulation of extracellular matrix and the abnormal behavior of epithelial cells and fibroblasts.The Hedgehog pathway (HH) plays a crucial role in embryonic development. In the fetal lung development, the HH pathway is involved in the epithelial-fibroblast interactions and controls the proliferation and differentiation of the mesenchyme. The HH pathway has been implicated in the fibrogenesis, particularly in the liver and kidney.The aim of this thesis was to characterize the HH pathway in pulmonary fibrosis in humans and in a model of bleomycin-induced fibrosis in mice.We demonstrated that the HH pathway is reactivated in lung tissue of IPF patients and in the model of pulmonary fibrosis in mice. We have shown that TGF-β1 activated the HH pathway in human lung fibroblasts and that the pharmacological inhibition of the HH pathway at the level of GLI transcription factors, inhibited the effect of TGF-β1 in vitro. By contrast, these inhibitors did not protect alveolar epithelial cells from TGF-β1-induced epithelial-mesenchymal transition. In vivo, we have shown that treatment with Smoothened inhibitors did not protect mice from the development of fibrosis while GANT61, an inhibitor of the GLI interaction with DNA, inhibited fibrosis .In conclusion, our results demonstrate the involvement of the HH pathway in pulmonary fibrosis and open new therapeutic perspectives
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Villar, Gómez Ana. "Neumonitis por hipersensibilidad y fibrosis pulmonar: estudio etiológico y del perfil inflamatorio." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/459244.
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La neumonitis por hipersensibilidad es una enfermedad caracterizada por una desestructuración del parénquima pulmonar, como resultado de una reacción inflamatoria de causa inmunológica en respuesta a una extensa variedad de antígenos, provocando diferentes grados de desestructuración del parénquima pulmonar, tras una sensibilización previa. Los agentes etiológicos descritos se clasifican en antígenos aviares, microorganismos y agentes químicos, si bien hasta en un 25-60% de los casos no es posible identificar el antígeno causal. Este hecho tiene una relevancia clínica especial, dado que la identificación del antígeno causal se ha demostrado como factor independiente relacionado con la supervivencia en la NH. Un interrogatorio exhaustivo acerca de posibles fuentes antigénicas, asi como la búsqueda de exposiciones ambientales ocultas, son piezas clave para aumentar las probabilidades del diagnóstico de NH. Pese a ello, el diagnostico de NH continua siendo en la actualidad complejo, debido a la falta de criterios diagnósticos validados. En este sentido, la introducción de test inmunológicos, como la determinación de anticuerpos IgG específicos en suero frente a proteínas aviares y/o fúngicas, y la práctica de una PIE, pueden ser de gran valor para establecer el diagnóstico de la enfermedad que además, puede presentar hallazgos radiológicos y anatomopatológicos inespecíficos, y en ocasiones simular a otras patologías.
El primer capítulo de esta tesis, demostró que hasta casi la mitad de los pacientes que cumplían criterios diagnósticos de FPI siguiendo las actuales guías internacionales (ATS 2011) tienen un diagnóstico de NH. La exposición a plumas ocultas en el ambiente domestico fue la causa de la enfermedad en el 63% de los casos. Nuestros resultados apoyarían la inclusión de un cuestionario específico para detectar una exposición antigénica oculta en el ambiente domestico, a la lista de exposiciones potencialmente causales de enfermedad pulmonar intersticial, FPI y NH.
El segundo capítulo analiza por primera vez el perfil inflamatorio del EI en dos grupos de pacientes con NH secundaria a diferentes antígenos. Los resultados muestran un patrón neutrófilico basal similar en NH secundarias a antígeno aviar o fúngico, si bien tras la exposición al antígeno casual, los pacientes con NH secundaria a exposición fúngica presentan un incremento en el porcentaje de neutrófilos y citoquinas proinflamatorias, mientras que aquellos con NH secundaria a exposición aviar muestran un aumento en el porcentaje de eosinófilos y citoquinas Th2. Estos resultados conducen a la hipótesis de que diferentes antígenos pueden condicionar el desarrollo de NH por diferentes mecanismos.Hypersensitivity pneumonitis (HP) is a disease characterized by a disruption of the pulmonary parenchyma as a result of an inflammatory reaction of immunological cause in response to a wide variety of antigens, causing different degrees of disruption of the lung parenchyma after previous sensitization. The aetiological agents described are classified into avian antigens, microorganisms and low molecular weight chemical agents, although in up to 25-60% of cases it is not possible to identify the causal antigen. This fact has a special clinical relevance, since the identification of the causal antigen has been demonstrated as an independent factor related to survival in HP. A thorough questioning of possible antigenic sources, as well as the search for ocult environmental exposures, are key to increasing the chances of HP diagnosis. In spite of this, the diagnosis of HP continues to be complex, due to the lack of validated diagnostic criteria. In this sense, the introduction of immunological tests, such as the determination of serum-specific IgG antibodies against avian and / or fungal proteins, and the practice of a SIC, can be of great value in establishing the diagnosis of the disease, wich may present nonspecific radiological and anatomopathological findings, and sometimes simulate other pathologies. The Chapter 1 of this thesis, showed that up to almost half of the patients who fulfilled the diagnostic criteria of IPF following the current international guidelines (ATS 2011) have a diagnosis of HP. Exposure to occult feathers in the domestic environment was the cause of the disease in 63% of cases. Our results would support the inclusion of a specific questionnaire to detect a hidden antigenic exposure in the domestic environment, to the list of potentially causal exposures of interstitial lung disease, IPF and HP. The Chapter 2 analyzes for the first time the inflammatory profile of induced sputum in two groups of patients with HP secondary to different antigens. The results show a similar basal neutrophilic pattern in HP secondary to avian or fungal antigen, although after exposure to the casual antigen, patients with HP secondary to fungal exposure present an increase in the percentage of proinflammatory neutrophils and cytokines, while those with HP secondary to avian exposure show an increase in the percentage of eosinophils and Th2 cytokines. These results lead to the hypothesis that different antigens can condition the development of HP by different mechanisms.
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Henaoui, Imène-Sarah. "MiR-199a-5p, un " fibromiR " amplificateur de la voie du TGF-beta dans la fibrose pulmonaire idiopathique." Phd thesis, Université Nice Sophia Antipolis, 2013. http://tel.archives-ouvertes.fr/tel-00931984.
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La Fibrose Pulmonaire idiopathique (FPI) est une maladie fibroproliférative pour laquelle il n'existe aucun traitement efficace. Les mécanismes à l'origine de cette pathologie sont méconnus et impliquent plusieurs types cellulaires et facteurs de croissance, comme le TGF-β responsable de la différenciation de fibroblastes en myofibroblastes. Pour mieux comprendre ces mécanismes physiopathologiques, nous nous sommes intéressés à l'implication des miARN dans ce processus. Une analyse par puces à ADN de l'ensemble des miARN modulés dans des échantillons pulmonaires de souris, résistantes ou sensibles à la fibrose pulmonaire induite par la bléomycine, nous a permis d'identifier miR-199a-5p comme le meilleur candidat associé à la fibrose pulmonaire mais aussi fibrose rénale et hépatique. J'ai ensuite démontré que l'expression de miR-199a-5p était induite par le TGF-β in vitro, et que sa surexpression ectopique induisait la différenciation des fibroblastes. Une combinaison d'approche in silico et expérimentale, m'a permis d'identifier la Cavéoline-1 (CAV-1) comme cible de ce miARN. La CAV-1 est impliquée dans la dégradation du récepteur TGF-β. Ainsi, l'inhibition de CAV-1 par miR-199a-5p constitue une boucle de rétrocontrôle positif exacerbant la voie TGF-β. De manière intéressante, l'inhibition de miR-199a-5p in vitro régule la différenciation, la prolifération et la migration des fibroblastes pulmonaires par le TGF-β. Par ailleurs, nos résultats précliniques indiquent que l'inhibition de ce miARN diminue les marqueurs de fibrose, permettant d'envisager le développement de nouvelles approches thérapeutiques dans le traitement de la FPI et d'autres maladies fibroprolifératives.
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Fernandez, Isis E. [Verfasser], and Oliver [Akademischer Betreuer] Eickelberg. "Biomarker discovery and drug testing in Idiopathic Pulmonary Fibrosis / Isis E. Fernandez ; Betreuer: Oliver Eickelberg." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1174142707/34.
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Skwarna, Sylwia [Verfasser]. "Role of Bcl-xL in HGF-elicited epithelial protection in idiopathic pulmonary fibrosis / Sylwia Skwarna." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1068874740/34.
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Akram, Khondoker Mehedi. "Idiopathic pulmonary fibrosis : exploration of aberrant epithelial wound repair and stem cell-mediated regenerative approaches." Thesis, Keele University, 2013. http://eprints.keele.ac.uk/3804/.
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Idiopathic pulmonary fibrosis (IPF) is a fatal form of fibrotic lung disease. The pathogenesis of IPF is unclear. An aberrant alveolar epithelial wound repair is likely to be involved in the disease process. Alveolar bronchiolisation, a process where bronchiolar Clara cells migrate into the affected alveoli, is a manifestation of abnormal alveolar wound repair. The role of Clara cells during alveolar injury repair in IPF is controversial. This study was undertaken to investigate the role of Clara cells in alveolar epithelial wound repair and pulmonary fibrosis. Currently, there is no curative treatment for IPF; therefore, stem-cell mediated regenerative therapy has been suggested. In this study, the paracrine role hMSC and hESC on pulmonary epithelial wound repair has also been evaluated. A direct-contact co-culture in vitro model was utilised to evaluate the role of Clara cells on alveolar epithelial cell wound repair. Immunohistochemistry was conducted on IPF lung tissue samples to replicate the in vitro findings ex vivo. The paracrine role of hMSC and hESC on pulmonary epithelial cells was evaluated by utilising the in vitro wound repair system. This study demonstrates that Clara cells induce apoptosis in AEC through a TRAILdependent mechanism, resulting in significant inhibition of wound repair. Furthermore in the IPF lungs, TRAIL-expressing Clara cells were detected within the fibrotic alveoli, together with widespread AEC apoptosis. This study also demonstrates that hMSC enhance AEC and SAEC wound repair via a paracrine mechanism through stimulation of cell migration; whereas, secretory factors of differentiated hESC promote AEC wound repair through stimulation of both cell proliferation and migration. Through this study I propose a novel hypothesis which implies that the extensive profibrotic remodelling associated with IPF could be driven by TRAIL-expressing Clara cells inducing AEC apoptosis through a TRAIL-dependent mechanism. My study also supports the notion of clinical application of hMSC and hESC or their secretory products as regenerative therapeutic modality for IPF.
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Ware, Tierra A. "Epigenetic and Pten Regulation of Longevity Pathways Related to Idiopathic Pulmonary Fibrosis and Organismal Aging." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480598045664191.
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Bellamri, Nessrine. "Le macrophage dans la fibrose pulmonaire idiopathique : effets du nintédanib et expression du biomarqueur pronostique CXCL13." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B067.
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Le nintédanib (NTD), un médicament antifibrosant, ralentit le déclin de la fonction respiratoire chez les patients atteints de fibrose pulmonaire idiopathique (FPI). Le NTD exerce ses effets antifibrosants en inhibant l’activité cellulaire de différentes protéines à tyrosine kinase. Le NTD inhibe également l’activité kinase de la protéine humaine recombinante CSF-1R. Ce récepteur, exprimé par les cellules myéloïdes, contrôle différentes fonctions du macrophage. Cellule immunitaire résidente ou différenciée à partir du monocyte, le macrophage contribue au développement de la fibrose pulmonaire en secrétant des molécules pro-inflammatoires et pro-fibrosantes. Un premier objectif de mes travaux de thèse a été de déterminer si, en bloquant l’activité de CSF1-R, le NTD altère les propriétés in vitro du macrophage humain différencié à partir du monocyte circulant (MDM) par le CSF-1. Nos résultats démontrent que le NTD inhibe la phosphorylation et l’activité de CSF-1R dans le MDM, à de faibles concentrations équivalentes à celles bloquant l’activité de la protéine recombinante. En réduisant l’activité de CSF-1R, le NTD diminue l’adhérence du macrophage et l’expression de la chimiokine pro-fibrosante CCL2. De plus, en bloquant l’activité de CSF-1R et celles d’autres cibles moléculaires, le NTD altère la polarisation des MDM en macrophages M1 et M2. Il réduit la production de diverses interleukines et chimiokines par le macrophage M1 et prévient l’expression de marqueurs membranaires par le macrophage M2. Nos résultats démontrent en particulier que le NTD réduit l’expression de CXCL13, un biomarqueur pronostique de la FPI. Cette chimiokine est exprimée dans le tissu pulmonaire mais son origine cellulaire reste incertaine. Le second objectif de mes travaux de thèse a donc été de caractériser l’expression de CXCL13 dans le macrophage pulmonaire. Nos résultats démontrent que CXCL13 est exprimé par les macrophages alvéolaires de patients atteints de FPI. In vitro, l’expression de CXCL13 dans le macrophage alvéolaire et dans le MDM activé est induite par le TNF-α et l’IL-10, via l’activation respective des voies de signalisation NF-κB et JAK/STAT. Nous montrons que les concentrations sériques de CXCL13, de TNF-α et d’IL-10 sont significativement corrélées entre elles chez les patients atteints de FPI. Ces résultats suggèrent donc que le TNF-α et l’IL-10 peuvent contrôler l’expression de CXCL13 chez ces patientsNintedanib (NTD) is an antifibrotic drug that decreases the decline of the respiratory function of patients suffering from idiopathic pulmonary fibrosis (IPF). NTD exerts antifibrotic effects by inhibiting cellular activity of various tyrosine kinase proteins. It also prevents the activity of the human recombinant CSF-1R protein that is expressed by myeloid cells, especially macrophages. Resident cells or différentiated from circulating monocytes, the macrophages contribute to IPF by secreting several proinflammatory and profibrotic cytokines. In this context, the first objective of my thesis was to determine, if by inhibiting CSF-1R activity, NTD could alter the functions of human macrophages differentiated from blood monocytes (MoDM) by CSF-1 (also called M-CSF). Our results demonstrate that NTD blocks the phosphorylation and the activity of CSF-1R in CSF-1-activated MoDM at very low concentrations that are similar to those inhibiting the human recombinant protein. By preventing CSF-1R activity, NTD reduces cell adhesion and expression of the profibrotic chemokine CCL2. Moreover, by blocking the activity of CSF1R and that of other molecular targets, NTD modulates the polarization of CSF-1-activated MoDM. It reduces the production of various interleukins and chemokines by M1 MoDM and prevents the membrane expression of M2 markers. Our results notably demonstrate that NTD significantly inhibits the expression of CXCL13, a prognostic biomarker of IPF. This chemokine is expressed in pulmonary tissues but its cellular origin is unclear. The second objective of my thesis was thus to characterize CXCL13 expression in pulmonary macrophages. Our results demonstrate that CXCL13 is expressed by alveolar macrophages in patients with IPF. In vitro, CXCL13 expression in activated alveolar macrophages and MoDM is controlled by TNF-α and IL-10 through the activation of the NF-κB and JAK/STAT pathways, respectively. Moreover, we demonstrate that seric concentrations of TNF-α, IL-10 and CXCL13 are correlated in patients with IPF. These results thus suggest that TNF-α and IL-10 could mediate CXCL13 expression in those patients
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Shaba, Enxhi. "Functional proteomic investigation of extracellular vesicles: Rai +/+ vs Rai -/- astrocytes and released vesicles in EAE and bronchoalveolar lavage fluid-extracted extracellular vesicles in idiopathic pulmonary fibrosis." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1142528.
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In the recent years, extracellular vesicles (EVs) drew a growing interest in scientific community, especially for their intrinsic role of cell-cell communication entities between local and distant targets. Given these appealing features, functional proteomics of EVs is a considerably valuable approach for the investigation of not only their functions, but also of their potentialities, as it provides a wider and enriched scenario of various physio-pathological molecular mechanisms. Considering this background, we performed two different functional proteomic studies on EVs in two different pathologic conditions.
The first study emerged from recent investigations on protein ShcC/Rai role in experimental autoimmune encephalomyelitis (EAE), as its deficiency resulted in disease protection and astrocytes were identified as accountable for the establishment of a local protective environment. Therefore, our analysis focused on the differences in protein content of astrocytes, as well as of their released extracellular vesicles, between Rai+/+ and Rai -/- in a not stimulated and IL-17-stimulated conditions, applying 2DE, image analysis, mass spectrometry identification of differential proteins and enrichment analysis. Curiously, our proteomic data showed that both the vesicular and cellular differential proteins indicate the overall involvement of macro molecular areas, such as oxidative stress response, ECM and cellular remodelling, glutamate metabolism, EMT mechanisms and metabolic reprogramming, shifting astrocytes towards a neuroprotective response.
Concurrently, a second study was conducted to characterize and explore the individual impact on Idiopathic Pulmonary Fibrosis (IPF) pathogenesis of not only the vesicular component of bronchoalveolar lavage fluid (BALF), but also its fluid counterpart. Indeed, to the best of our knowledge, our study is the first shotgun proteomic investigation of EV isolated from BALF of IPF patients. To this purpose, ultracentrifugation was chosen as EVs isolation technique and its purification was assessed by TEM, 2DE and LC-MS/MS. Interestingly, our 2DE data and scatter plot analysis showed a considerable difference of EVs proteome with respect to whole BALF and to its fluid counterpart proteome, highlighting the importance of pre-fractioning of complex samples to the advantage of low-abundant protein species in biomarkers discovery. Remarkably, enrichment analysis results draw attention on a systemic metabolic dysregulation in disease development and highlight relevant molecular pathways that result distinctive but complementary in IPF pathogenesis.
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Balsara, Nisha [Verfasser]. "Role of the WNT/beta-catenin signal pathway in idiopathic and experimental pulmonary fibrosis / Nisha Balsara." Gießen : Universitätsbibliothek, 2013. http://d-nb.info/1065320469/34.
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Nicol, Lisa Margaret. "Diagnostic and prognostic value of current phenotyping methods and novel molecular markers in idiopathic pulmonary fibrosis." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33098.
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Background Idiopathic pulmonary fibrosis (IPF) is a devastating form of chronic lung injury of unknown aetiology characterised by progressive lung scarring. A diagnosis of definite IPF requires High Resolution Computed Tomography (HRCT) appearances indicative of usual interstitial pneumonia (UIP), or in patients with 'possible UIP' CT appearances, histological confirmation of UIP. However the proportion of such patients that undergo SLB varies, perhaps due to a perception of risk of biopsy and additive diagnostic value of biopsy in individual patients. We hypothesised that an underlying UIP pathological pattern may result in increased risk of death and aimed to explore this by comparing the risk of SLB in suspected idiopathic interstitial pneumonia, stratified according to HRCT appearance. Additionally we sought to determine the positive-predictive value of biopsy to diagnose IPF in patients with 'possible UIP HRCT' in our population. In patients with possible UIP who are not biopsied, the clinical value of bronchoalveolar lavage (BAL) is uncertain. We aimed to prospectively study the diagnostic and prognostic value of BAL differential cell count (DCC) in suspected IPF and determine the feasibility of repeat BAL and the relationship between DCC and disease progression in two successive BALs. We hypothesised that BAL DCC between definite and possible IPF was different and that baseline DCC and change in BAL DCC predicted disease progression. Alveolar macrophages (AMs) are an integral part of the lung's reparative mechanism following injury, however in IPF they contribute to pathogenesis by releasing pro-fibrotic mediators promoting fibroblast proliferation and collagen deposition. Expansion of novel subpopulations of pulmonary monocyte-like cells (PMLCs) has been reported in inflammatory lung disease. We hypothesised that a distinct AM polarisation phenotype would be associated with disease progression. We aimed to perform detailed phenotyping of AM and PMLCs in BAL in IPF patients. Several prognostic scoring systems and biomarkers have been described to predict disease progression in IPF but most were derived from clinical trial patients or tertiary referral centres and none have been validated in separate cohorts. We aimed to identify a predictive tool for disease progression utilising physiological, HRCT and serum biomarkers in a unique population of incident treatment naïve IPF patients. Methods Between 01/01/07 and 31/12/13, 611 consecutive incident patients with suspected idiopathic interstitial pneumonia (IIP) presented to the Edinburgh lung fibrosis clinic. Of these patients 222 underwent video-assisted thoracoscopic lung biopsy and histological pattern was determined according to ATS/ERS criteria. Post-operative mortality and complication rates were examined. Fewer than 2% received IPF-directed therapy and less than 1% of the cohort were lost to follow-up. Disease progression was defined as death or ≥10% decline in VC within 12 months of BAL. Cells were obtained by BAL and a panel of monoclonal antibodies; CD14, CD16, CD206, CD71, CD163, CD3, CD4, CD8 and HLA-DR were used to quantify and selectively characterise AMs, resident PMLCs, inducible PMLCs, neutrophils and CD4+/CD8+ T-cells using flow cytometry. Classical, intermediate and non-classical monocyte subsets were also quantified in peripheral blood. Potential biomarkers (n=16) were pre-selected from either previously published studies of IPF biomarkers or our hypothesis-driven profiling. Linear logistic regression was used on each predictor separately to assess its importance in terms of p-value of the associated weight, and the top two variables were used to learn a decision tree. Results Based on the 2011 ATS/ERS criteria, 87 patients were categorised as 'definite UIP', of whom 3 underwent SLB for clinical indications. IPF was confirmed in all 3 patients based on 2013 ATS/ERS/JRS/ALAT diagnostic criteria. 222 patients were diagnosed with 'possible UIP'; 55 underwent SLB, IPF was subsequently diagnosed in 37 patients, 4 were diagnosed with 'probable IPF' and 14 were considered 'not IPF'. In this group, 30 patients were aged 65 years or over and 25/30 (83%) had UIP on biopsy. 306 patients had HRCTs deemed 'inconsistent with UIP', SLB was performed in 168 patients. Post6 operative 30-day mortality was 2.2% overall, and 7.3% in the 'possible UIP' HRCT group. Patients with 'definite IPF' based on HRCT and SLB appearances had significantly better outcomes than patients with 'definite UIP' on HRCT alone (P=0.008, HR 0.44 (95% CI 0.240 to 0.812)). BAL DCC was not different between definite and possible UIP groups, but there were significant differences with the inconsistent with UIP group. In the 12 months following BAL, 33.3% (n=7/21) of patients in the definite UIP group and 29.5% (n=18/61) in the possible UIP group had progressed. There were no significant differences in BAL DCC between progressor and non-progressor groups. Mortality in patients with suspected IPF and a BAL DCC consistent with IPF was no different to those with a DCC inconsistent with IPF (P=0.425, HR 1.590 (95% CI 0.502 to 4.967)). There was no difference in disease progression in either group (P=0.885, HR 1.081 (95% CI 0.376 to 3.106)). There was no statistically significant difference in BAL DCC at 0 and 12 months in either group. There was no significant change in DCC between 0 and 12 month BALs between progressors and non-progressors. Repeat BAL was well tolerated in almost all patients. There was 1 death within 1 month of a first BAL and 1 death within 1 month of a second BAL; both were considered 'probably procedure-related'. AM CD163 and CD71 (transferrin receptor) expression were significantly different between groups (P < 0.0001), with significant increases in the IPF group vs non fibrotic ILD (P < 0.0001) and controls (P < 0.0001 and P < 0.001 respectively). CD71 expression was also significantly increased in the IPF progressor vs non-progressor group (P < 0.0001) and patients with high CD71 expression had significantly poorer survival than the CD71low group (P=0.040, median survival 40.5 and 75.6 months respectively). CD206 (mannose receptor) expression was also significantly higher in the IPF progressor vs non-progressor group (P=0.034). There were no differences in baseline BAL neutrophil, eosinophil or lymphocyte percentages between IPF progressor or non-progressor groups. The percentage of rPMLCs was significantly increased in BAL fluid cells of IPF patients compared to those with non-fibrotic ILD (P < 0.0001) and healthy controls (P < 0.05). Baseline rPMLC percentage was significantly higher in IPF progressors vs IPF non-progressors (P=0.011). Baseline BAL iPMLC:rPMLC ratio was also significantly different between IPF progressor and non-progressor groups (P=0.011). Disease progression was confidently predicted by a combination of clinical and serological variables. In our cohort we identified a predictive tool based on two key parameters, one a measure of lung function and one a single serum biomarker. Both parameters were entered into a decision tree, and when applied to our cohort yielded a sensitivity of 86.4%, specificity of 92.3%, positive predictive value of 90.5% and negative predictive value of 88.9%. We also applied previously reported predictive tools such as the GAP Index, du Bois score and CPI Index to the Edinburgh IPF cohort. Conclusions SLB can be of value in the diagnosis of ILD, however perhaps due to the perceived risks associated with the procedure, only a small percentage of patients undergo SLB despite recommendations that patients have histological confirmation of the diagnosis. Advanced age is a strong predictor for IPF, and in our cohort 83% of patients aged over 65 years with 'possible UIP' HRCT appearances, had UIP on biopsy. BAL and repeat BAL in IPF is feasible and safe (< 1.5% mortality). Of those that underwent repeat BAL, disease progression was not associated with a change in DCC. However, 22% of lavaged patients died or were deemed too frail to undergo a second procedure at 12 months. These data emphasise the importance of BAL in identifying a novel human AM polarisation phenotype in IPF. Our data suggests there is a distinct relationship between AM subtypes, cell-surface expression markers, PMLC subpopulations and disease progression in IPF. This may be utilised to investigate new targets for future therapeutic strategies.Disease progression in IPF can be predicted by a combination of clinical variables and serum biomarker profiling. We have identified a unique prediction model, when applied to our locally referred, incident, treatment naïve cohort can confidently predict disease progression in IPF. IPF is a heterogeneous disease and there is a definite clinical need to identify 'personalised' prognostic biomarkers which may in turn lead to novel targets and the advent of personalised medicines.
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Dakhlallah, Duaa. "Cross-Talk Between Epigenetic Regulation And Mir-17~92 Cluster Expression In Idiopathic Pulmonary Fibrosis (IPF)." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1297960869.
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Barratt, Shaney Louise. "Investigation into the role of vascular endothelial growth factor in the development of idiopathic pulmonary fibrosis." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.688106.
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Vascular Endothelial Growth Factor (VEGF-A), has been implicated in the pathogenesis of many chronic lung diseases including Idiopathic Pulmonary Fibrosis (IPF) in which failure of essential tissue repair occurs. Here it is demonstrated that IPF is associated with an increased expression of an antiangiogenic VEGF-A splice variant in both IPF lung tissue and isolated IPF lung fibroblasts. In a mouse model of pulmonary fibrosis, alveolar type two cell (ATII) specific deficiency of VEGF-A or constitutive over-expression of VEGF-A165b inhibited the development of pulmonary fibrosis as did treatment with intraperitoneal delivery of VEGF-A16Sb to wild-type mice. These results indicate that changes in VEGF-A expression sourced from ATII cells, namely the ratio of VEGFAxxxa to VEGF-Axxxb, are critical in the development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.
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Nambiar, Shabarinath. "Unravelling the Lipidome of Idiopathic Pulmonary Fibrosis and its Spatial Distribution using High Resolution Mass Spectrometry." Thesis, Nambiar, Shabarinath (2018) Unravelling the Lipidome of Idiopathic Pulmonary Fibrosis and its Spatial Distribution using High Resolution Mass Spectrometry. PhD thesis, Murdoch University, 2018. https://researchrepository.murdoch.edu.au/id/eprint/43984/.
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Chronic lung diseases are complex, progressive disorders with increasing incidence and mortality. Chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis are examples of chronic lung conditions that can significantly impact the quality of life. Minimally-invasive diagnostic methods that eliminate bronchoscopic and surgical biopsy from patients are ideal; metabolomics therefore holds considerable promise for the discovery of biomarkers that can aid diagnosis and treatment with greater sensitivity, specificity and precision.
The main aim of this project was to employ ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-QTOF) high resolution mass spectrometry (HRMS) and matrix-assisted laser desorption ionisation (MALDI) mass spectral imaging (MSI) together with multivariate statistics-based metabolomics to identify and characterize potential lipid biomarkers of idiopathic pulmonary fibrosis (IPF). This dissertation consists of the following studies: (1) literature review of metabolomics in chronic lung diseases; (2) application of HRMS for untargeted metabolic profiling of chronic lung disease including COPD and IPF; (3) investigation of a novel data-independent acquisition (DIA) approach to augment untargeted approaches for lipid biomarker identification; (4) development of a novel matrix application technique to improve MALDI-MSI acquisitions of tissue sections whilst maintaining spatial localisation of endogenous metabolites; and (5) exploiting potassium adduct formation to resolve the spatial distribution of lipids in fibrotic tissues.
A total of 65 clinical plasma samples (from 20 healthy control subjects, 21 COPD and 24 IPF patients) were profiled using UHPLC-QTOF-MS. A fundamental challenge in using HRMS for untargeted profiling of complex, chronic lung diseases is the heterogeneity of the human samples. Various contaminations present in fibrotic tissues or adjacent non-fibrotic constituents can confound characterization and encumber the discovery of reliable biomarkers. The results of this study revealed significant correlation between COPD and IPF clinical phenotypes and plasma metabolite profiles. The unbiased metabolomics workflow and deconvolution pipeline provided end-to-end analysis from peak picking and annotation through to metabolite identification.
Subsequently, the ability of the UPLC-QTOF-MS method to discriminate between lipid species was enhanced by the application of a DIA method to distinguish between “stable versus progressor” IPF patients. This DIA method is known as SONAR and uses a wide, continuously sliding precursor window for fragmentation, thereby allowing correlation of precursor and fragment ions. SONAR lipid data were processed using Progenesis QI and searched against LIPID MAPS for structural elucidation and metabolite confirmation. The lipids identified were found to be intermediates of key metabolic pathways such as the glycolytic/TCA cycle, mitochondrial-beta oxidation and lipid metabolism and hold considerable promise as biomarkers of disease.
The matrix deposition step in MALDI-MSI is crucial for simultaneous extraction of metabolites from tissue sections as well as maintaining the spatial dimensionality of the endogenous metabolites. A novel, efficient and cost-effective preparative method referred to as the “freeze-spot” method was developed using wheat seed sections to demonstrate extraction efficiency and reliability, whilst maintaining the spatial resolution of the acquired MALDI-MSI images. The technique was also found to be simple and robust, forming fine matrix crystals that enabled efficient ionisation of surface metabolites, further eliminating the need for sophisticated matrix application approaches.
In the final study, 10 healthy and 10 fibrotic tissues were compared using MALDI-MSI. The MSI technique developed uses potassium adduct formation to improve spatial resolution and dimensionality of lipid species such as triglycerides (TG), ceramides, sphingolipids and glycerophospholipids. The results of this study showed changes in lipid composition of IPF tissues compared to healthy controls. This study identified lysophosphatidylcholine (LysoPC), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as potential lipid biomarkers of the disease and requires further study as targets of intervention and treatment. Both SONAR and MSI successfully identified similar classes of lipids (TG, PE, LysoPC and PC) which may play a role in the pathophysiology of the IPF lipidome.
This project highlighted the complementarity of HRMS and MSI based metabolomics for the characterization of unique lipid features in fibrotic tissue and plasma samples. The study also demonstrated the discriminative power of the unbiased DIA approach for the identification of lipids via fragment ion patterns that were indicative of specific lipid classes. In addition, the application of chemometric principal component analysis (PCA) and orthogonal partial least-squares to latent structures-direct analysis (OPLS-DA) proved useful for the identification of statistically significant lipids. This statistical approach allowed for the assessment of covariance and correlation between lipids and the modelled lung diseases, and further illustrated lipid compositional changes in chronic lung diseases.
Taken together, the experimental work presented in this thesis show the large potential for mass spectrometry-based metabolomics as a tool for discovery. The specificity of the novel methods outlined will be highly beneficial for compound identification and further confirmation of disease biomarkers.
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Bellaye, Pierre-Simon. "Rôle de la petite protéine de choc thermique alphaB crystallin dans la fibrogénèse pulmonaire et son implication dans la voie de signalisation du transforming growth factor - béta1." Thesis, Dijon, 2013. http://www.theses.fr/2013DIJOMU06/document.
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La fibrose pulmonaire idiopathique (FPI) est de pronostic sombre et sans traitement efficace. Elle est caractérisée par un début sous pleural et la présence de myofibroblastes responsables de la synthèse excessive de la matrice extracellulaire. La voie de signalisation du Transforming Growth Factor (TGF)-β1, facteur clé de la genèse de la fibrose et sa progression, passe par les Smads, notamment Smad4. Le TGF-β1 induit la différenciation des fibroblastes pulmonaires et des cellules épithéliales et mésothéliales en myofibroblastes. AB-crystallin est une protéine de choc thermique surexprimée dans la fibrose du foie, du rein et la fibrose vasculaire. Elle peut être induite par le TGF-β1. Dans ce travail, nous avons étudié le rôle d’αB-crystallin dans la fibrose pleurale et pulmonaire. Nous montrons qu’αB-crystallin est surexprimée dans les poumons et la plèvre de patients atteints de FPI. In vivo, dans trois modèles de fibrose pulmonaire (bléomycine, surexpression de TGF-β1 ou d’IL-1β) les souris KO pour αB-crystallin sont protégées de la fibrose avec une inhibition de la voie du TGF-β. In vitro, dans les cellules épithéliales, mésothéliales ou les fibroblastes, αB-crystallin augmente la localisation nucléaire de Smad4. En interagissant avec TIF1γ, responsable de l’export nucléaire de Smad4, elle favorise la séquestration nucléaire de Smad4 et son activité pro-fibrosante. Au contraire, son inhibition permet la formation du complexe Smad4/TIF1γ et l’export nucléaire de Smad4 inhibant son activité. Ce travail montre l’importance d’αB-crystallin dans la fibrose pleuro-pulmonaire et son rôle sur la voie du TGF-. AB-crystallin pourrait être une cible thérapeutique de la FPIIdiopathic pulmonary fibrosis (IPF) has no effective current treatment. It is characterized by a sub-pleural onset and the presence of myofibroblasts, responsible for the excessive extracellular matrix synthesis. Transforming Growth Factor (TGF)-β1 is considered as the major profibrotic cytokine. Its signaling pathway occurs through the Smads proteins, including Smad4. TGF-β1 allows the differentiation of lung fibroblasts and epithelial and mesothelial cells into myofibroblasts. AB-crystallin is a small heat shock protein overexpressed in liver, renal and vascular fibrosis and can be induced by TGF-β1. In this study, we assessed the role of αB-crystallin in pleural and pulmonary fibrosis. We show that αB-crystallin is overexpressed in the lung and the pleura of IPF patients. In vivo, in three pulmonary fibrosis models (bleomycin, TGF-β1 or IL-1β overexpression) αB-crystallin KO mice are protected from fibrosis with an inhibition of the TGF-β pathway. In vitro, in epithelial and mesothelial cells or fibroblasts, αB-crystallin increases Smad4 nuclear localization. Interacting with TIF1γ, responsible for the nuclear export of Smad4, it promotes the nuclear sequestration of Smad4 and thus its profibrotic activity. Instead, αB-crystallin inhibition allows the formation of the Smad4/TIF1γ complex and promotes Smad4 nuclear export an profibrotic activity. This work shows the importance of αB-crystallin in pleuro-pulmonary fibrosis and its role on the TGF-β1 pathway. AB-crystallin appears as a putative therapeutic target for IPF
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Cameli, Paolo. "The impact of antifibrotic therapy in the management of idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases: a real-world comparative study of efficacy between pirfenidone and nintedanib." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1159047.
Full textAbstract:
Background: Idiopathic pulmonary fibrosis (IPF) is the most common and lethal among diffuse fibrosing interstitial lung diseases (ILD). Beyond lung transplantion, the therapeutic approach relies on antifibrotic treatment: pirfenidone and nintedanib are the only pharmaceutical drugs approved for IPF, since they have demonstrated to significantly reduce disease progression rate. Still, no solid data has been published to compare these two drugs as well as few studies have investigated their potential efficacy on familial pulmonary fibrosis (FPF) and progressive fibrosing ILD (PF-ILD) in a real-life setting.
Methods: we collected clinical, functional and radiological data from all patients affected with IPF and PF-ILDs that have been treated with pirfenidone and nintedanib at Referral Centre of Siena from 2011 to 2020. The aim of the research was to compare effectiveness of the two drugs in terms of mortality and disease progression in our population.
Results: no significant differences in mortality and progression-free survival were observed between pirfenidone and nintedanib subgroup. Both drugs significantly reduce FVC and DLCO decline rate in respect with pretreatment period. Similar data was observed in the PF-ILD subgroup, while FPF patients showed no significant benefit from antifibrotic treatment in terms of disease progression. Pirfenidone was more effective than nintedanib in preserving FVC in FPF subgroup.
Conclusions: our research study, conducted in a large cohort through a almost decennial time of observation, confirmed the reliable and substantially similar efficacy of pirfenidone and nintedanib in improving life expectancy and progression-free survival of IPF patients. FPF appeared to be less
responsive to antifibrotics, but pirfenidone showed a better performance than nintedanib on this field. PF-ILD patients showed a analogue clinical course of IPF subjects in our study: the effectiveness of pirfenidone and nintedanib was reliable and similar, supporting their future use in clinical practice.
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Jabłońska, Ewa Danuta [Verfasser]. "Role of intrinsic coagulation pathway in the pathogenesis of idiopathic pulmonary fibrosis / vorgelegt von Jabłońska, Ewa Danuta." Giessen : VVB Laufersweiler Verlag, 2011. http://d-nb.info/1010853899/34.
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