Dissertations / Theses on the topic 'Airway remodelling'
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1
Leggett, Julian James. "Airway remodelling in asthma." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485059.
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Asthma management places significant financial demands on health services. With increased understanding of the mediators involved in asthma pathophysiology more specific agents could be developed for treatment. We studied the effects of oxidant injury- on adult asthmatic cells in vitro and showed asthmatic epithelium more susceptible to oxidative stress at high concentrations of hydrogen peroxide. Cell death occurred via caspase independent apoptosis. However, at lower doses of hydrogen peroxide proliferation was observed suggesting a biphasic response. We investigated levels of Matrix Metalloproteinase-9 (MMP-9) and its inhibitor Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) in the induced sputum, bronchial wash and bronchoalveolar lavage fluid (BALF) of adult asthmatics and their correlation to- their respective immunostaining in bronchial biopsies. Bronchoalveolar lavage fluid in asthmatics demonstrates significantly raised TIMP-1 levels suggesting derangement in extracellular matrix turnover. Involvement of TIMP-1 in asthma pathophysiology is further supported by the finding that TIMP-1 immunostaining correlated with markers of asthma severity. In contrast no such relationship was observed with MMP-9, suggesting an imbalance between MMP-9 and TIMP-1 may be important in remodelling 'of the airway in asthma. Increased Epithelial Growth Factor (EGF) staining was observed within the basal • controls. However, no difference in EGF levels between asthmatics and controls in epithelial layer and in submucosal macrophages of asthmatics compared to either BALF or bronchial wash was found. In the 'asthmatic subjects studied response. In conclusion, this data suggests the epithelial response to increased Epithelial Growth Factor Receptor (EGFR) correlated positively with PC20 suggesting that in mild asthma increased EGFR represents an appropriate repair EGFR expression in mild asthma appears appropriate. In summary, asthmatic bronchial epithelium demonstrates an altered response to oxidative stress. This thesis further supports the evidence for abnormal epithelial cell response in asthma to oxidative stress and an imbalance in matrix turnover in the asthmatic airway.
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Boustany, Sarah. "Mechanisms of Airway Remodelling." Thesis, The University of Sydney, 2008. http://hdl.handle.net/2123/3577.
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Asthma is an inflammatory disease characterised by tissue remodelling. A prominent feature of this remodelling is an increase in the number and size of the blood vessels- formed from pre-existing capillaries – angiogenesis (Siddiqui et al., 2007; Wilson, 2003). This is triggered by many different endogenous angiogenic stimulators such as vascular endothelial growth factor (VEGF), and inhibited by endogenous angiogenic inhibitors such as tumstatin. Tumstatin is the non-collagenous domain (NC1) of the collagen IV α3 chain which, when cleaved, inhibits endothelial cell proliferation and induces apoptosis. Experiments described in this thesis have for the first time demonstrated the absence of tumstatin in the airways of individuals with asthma and lymphangioleiomyomatosis (LAM) as well as the functional responses to tumstatin as an angiogenic inhibitor, both in vitro and in vivo, in the airway. Although tumstatin was absent from the airways of asthmatic and LAM individuals it was present in the airways of individuals with no airways disease, chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis. No significant difference was seen in the levels of the Goodpasture Binding Protein (GPBP), a phosphorylating protein responsible for the alternate folding of tumstatin, between asthmatic, LAM and individuals with no airways disease. The αvβ3 integrin, reported to be necessary for the activity of tumstatin, as well as the individual αv and β3 sub-units were shown to be equally expressed in the airways of all patient groups. Co-localisation of tumstatin, VEGF and the αvβ3 integrin was seen in the disease free airways, however, a different pattern of VEGF and the αvβ3 integrin expression was observed in asthmatic and LAM airways with minimal co-localisation. Tumstatin was detected in serum and bronchoalveolar lavage fluid (BAL-f) samples from asthmatics and individuals with no airway disease, however there was no significant difference in the level of expression between the two groups. It was demonstrated that the tumstatin detected in the serum and BAL-f samples from asthmatics and individuals with no airway disease was part of the whole collagen IV α3 chain and not in its free and potentially active form. The ability of recombinant tumstatin to inhibit tube formation and proliferation of primary pulmonary endothelial cells was demonstrated for the first time. Further, the functional response of tumstatin was demonstrated in vivo in a mouse model of allergic airway disease. Tumstatin inhibited angiogenesis in the airway and decreased airway hyperresponsiveness. Whether there is potential for tumstatin, or a derivative thereof, to be of therapeutic value in airways diseases in which angiogenesis is a component should be the subject of future studies.
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Boustany, Sarah. "Mechanisms of Airway Remodelling." University of Sydney, 2008. http://hdl.handle.net/2123/3577.
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Doctor of Philosophy (PhD)Asthma is an inflammatory disease characterised by tissue remodelling. A prominent feature of this remodelling is an increase in the number and size of the blood vessels- formed from pre-existing capillaries – angiogenesis (Siddiqui et al., 2007; Wilson, 2003). This is triggered by many different endogenous angiogenic stimulators such as vascular endothelial growth factor (VEGF), and inhibited by endogenous angiogenic inhibitors such as tumstatin. Tumstatin is the non-collagenous domain (NC1) of the collagen IV α3 chain which, when cleaved, inhibits endothelial cell proliferation and induces apoptosis. Experiments described in this thesis have for the first time demonstrated the absence of tumstatin in the airways of individuals with asthma and lymphangioleiomyomatosis (LAM) as well as the functional responses to tumstatin as an angiogenic inhibitor, both in vitro and in vivo, in the airway. Although tumstatin was absent from the airways of asthmatic and LAM individuals it was present in the airways of individuals with no airways disease, chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis. No significant difference was seen in the levels of the Goodpasture Binding Protein (GPBP), a phosphorylating protein responsible for the alternate folding of tumstatin, between asthmatic, LAM and individuals with no airways disease. The αvβ3 integrin, reported to be necessary for the activity of tumstatin, as well as the individual αv and β3 sub-units were shown to be equally expressed in the airways of all patient groups. Co-localisation of tumstatin, VEGF and the αvβ3 integrin was seen in the disease free airways, however, a different pattern of VEGF and the αvβ3 integrin expression was observed in asthmatic and LAM airways with minimal co-localisation. Tumstatin was detected in serum and bronchoalveolar lavage fluid (BAL-f) samples from asthmatics and individuals with no airway disease, however there was no significant difference in the level of expression between the two groups. It was demonstrated that the tumstatin detected in the serum and BAL-f samples from asthmatics and individuals with no airway disease was part of the whole collagen IV α3 chain and not in its free and potentially active form. The ability of recombinant tumstatin to inhibit tube formation and proliferation of primary pulmonary endothelial cells was demonstrated for the first time. Further, the functional response of tumstatin was demonstrated in vivo in a mouse model of allergic airway disease. Tumstatin inhibited angiogenesis in the airway and decreased airway hyperresponsiveness. Whether there is potential for tumstatin, or a derivative thereof, to be of therapeutic value in airways diseases in which angiogenesis is a component should be the subject of future studies.
4
Zhao, Jingyue. "Th17 responses in airway inflammation and airway remodelling." Thesis, King's College London (University of London), 2011. http://kclpure.kcl.ac.uk/portal/en/theses/th17-responses-in-airway-inflammation-and-airway-remodelling(94ca2e63-6304-4694-998e-b40747ca0f9a).html.
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McConnell, William David. "Mediators of airway remodelling in asthma." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288445.
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Beckett, P. A. "Pharmacology of airway remodelling in asthma." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596514.
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Grainge, Christopher. "Determinants of airway remodelling in asthma." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/384164/.
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Hilliard, Thomas Norman. "Airway inflammation and remodelling in cystic fibrosis." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427686.
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Daud, Tariq. "The role of WNT5a in airway remodelling in asthmatic airway epithelial repair." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42778.
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Asthma is heterogeneous disease characterised by distinct tissue molecular phenotypes (Choy et al, 2015). However, the process of repair and remodelling remains ambiguous in this context. Although previous reports have shown elevated protein and mRNA expression of WNT5a, there is limited evidence in the literature to the major source of and function of WNT5a in asthma. Furthermore, WNT5a acting through the non-canonical axis exhibits functional cross talk with TGF-β1, which may influence repair and remodelling in asthma. We sought to evaluate protein expression of WNT5a and TGF-β1 in bronchial biopsies from a previously described cohort of subjects (9 healthy and 23 asthmatics) in whom aggregate gene signature profiles for Th2 and Th17 activity from tissue homogenates were available. After observing co-localised protein expression of both WNT5a and TGF-b1 in the epithelium, further investigations in BEAS-2B cells as a basal cell wound repair model were undertaken. We observed increased WNT5a protein expression pattern in vivo in asthma. WNT5a protein expression was significantly elevated in the epithelium in Th17 gene expression high asthmatic biopsies and the lamina propria, but not the airway smooth muscle bundle. We found a significant correlation and colocalisation of protein expression between TGF-β1 and WNT5a immunostaining in the epithelium suggestive of crosstalk. Further evidence supportive of cross talk was that both TGF-β1 and WNT5a were shown to induce SMAD2/3 nuclear translocation, which was inhibited by BOX-5 (a WNT5a inhibitor). Furthermore, WNT5a increased [Ca2+]I suggestive of noncanonical pathway engagement. Lastly, both WNT5a and TGF-β1 dual stimulation increased wound closure in BEAS-2B cells. Finally, stimulation of BEAS-2B cells with either TGF-β1 or WNT5a increased the expression of epithelial-mesenchymal transition (EMT) markers. WNT5a protein is increased in the airway epithelium in patients with asthma displaying a mucosal Th17-dependent gene signature. Additionally, we show potential in vitro evidence of TGF-β1-WNT5a cross talk via the SMAD2/3 axis, promoting EMT and epithelial wound closure. This study potentially highlights a novel crosstalk pathway between WNT5a-TGF-β1 as a possible epithelial repair mechanism employed in asthma that warrants further molecular and functional characterisation.
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Zheng, Ling 1958. "Airway inflammation and remodelling post human lung transplantation." Monash University, Dept. of Medicine, 2002. http://arrow.monash.edu.au/hdl/1959.1/8099.
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Faiz, Alen. "Novel gene candidates for Airway Remodelling in Asthma." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/10448.
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Asthma is a complex chronic inflammatory disease regulated by the interplay of a large number of underlying mechanisms which contribute to the overall pathology. A number of structural changes occur in the asthmatic airways including increase in the mass of airway smooth muscle, angiogenesis and mucus hypersecretion which is collectively known as airway remodelling. The experiments in this thesis have for the first time directly compared airway smooth muscle (ASMC) gene expression profiles from asthmatic and healthy patients with the aim to identify genes contributing to asthma and airway remodelling. The latrophilin family members and CCL20 were identified as being up-regulated in asthmatic ASMC compared to healthy controls under basal and inflammatory conditions, respectively. CCL20 was up regulated by moderate asthmatic ASMC and sputum concentrations of CCL20 were found to inversely correlate with lung function. LPHN1 and 3 were found to be up-regulated in ASMC and were found to play a key role in the hyper contractility and increased abundance of ASM mass in the asthmatic airway. The findings present in this thesis have enhanced our understanding of the genes involved in the remodelling process in asthma and identified potential gene targets for future therapies.
12
Sammut, David. "Airway remodelling in asthma : aspects of airway wall thickness and extracellular matrix production." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/404048/.
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Khan, Nazmin. "The role of anaphylatoxins in asthma and airway remodelling." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-anaphylatoxins-in-asthma-and-airway-remodelling(ee2de1d0-eb02-4b19-b546-2d4c26d4bbef).html.
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C3a and C5a anaphylatoxins are proinflammatory polypeptides released during complement activation. They exert their biological functions by interacting with the G protein-coupled receptors, C3aR and C5aR respectively. Activation of the complement system has been implicated in the pathogenesis of many inflammatory diseases including asthma. Little is known, however, about the expression and location of complement components in asthmatic airways. -- Experiments described in this thesis demonstrate the expression and localisation of certain complement components and their two receptors in the bronchial mucosa. C3a and C5a-stimulated production of remodelling mediators and the biological function of the anaphylatoxins on the structural cells was also assessed. -- Immunohistochemical analysis revealed elevated expression/deposition of C3 and C5 components in the epithelium, airway smooth muscle and submucosa of asthmatics compared with controls, and also demonstrated expression of the two complement receptors on airways structural cells, including airway epithelial cells, endothelial cells, fibroblasts and smooth muscle cells (SMC). -- In general C3a was the more effective of the two anaphylatoxins in inducing structural cellular proliferation: C3a increased fibroblast and endothelial cell proliferation at a range of concentrations embracing the physiological, although it increased SMC proliferation only at the highest concentration (10~7 M) employed, and epithelial cell proliferation only at the lowest concentration (10~9 M) employed. C5a induced fibroblast proliferation but had no effect in this regard on the other structural cells.
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Davies, Elizabeth R. "Elucidating the role of ADAM33 in airway inflammation and remodelling in asthma." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/415835/.
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Asthma is a heterogeneous chronic inflammatory disease characterised by recurrent, reversible airflow obstruction, bronchial hyperresponsiveness (BHR) and airway remodelling. Impaired lung function in childhood asthma has been associated with polymorphisms in ADAM33. Soluble ADAM33 (sADAM33) is increased in bronchial lavage fluid (BALF) from asthmatics and is inversely correlated with FEV1. sADAM33 is induced by TGF-β present in asthmatic lungs, and promotes angiogenesis. ADAM33 expression is developmentally regulated and is influenced by maternal allergy via IL-13. This thesis will examine the hypothesis that alteration in the expression of ADAM33 will influence lung structure, affecting vessel and smooth muscle formation and these subsequent changes will impact on pulmonary function in airway inflammation. In DOX inducible Il-13 transgenic mice, significant neutrophilic inflammation and goblet cell metaplasia were observed. BHR was induced after methacholine challenge and IHC showed increased bronchial smooth muscle. Similarly, in human embryonic and juvenile mouse lungs, IL-13 suppressed Adam33 mRNA but not Acta2. ADAM33 was identified in BALF of the overexpressing mice. ADAM33 enzymatic activity was also significantly increased. In the ADAM33 transgenic model, induction of ADAM33 resulted in enzymatically active sADAM33 in BALF. ADAM33 significantly increased the expression of fibrotic markers suggesting regulation of pulmonary myogenesis, fibrogenesis, and angiogenesis. Consistent with this, immunofluorescence revealed airway remodelling with increased smooth muscle, collagen deposition and vessel formation in ADAM33 mice. In contrast, inflammatory cell counts in BALF, expression of inflammatory mediators and mucus related genes were not altered by ADAM33. In Adam33 -/- challenged with HDM, there was less BHR and eosinophilic and neutrophilic inflammation compared to Adam33 +/+. HDM caused suppression of Adam33 mRNA as well as ectodomain shedding of ADAM33 protein in BALF of wildtype mice that was absent in Adam33 -/-. The study provides novel data showing expression of sADAM33 in airways to induce myogenesis, fibrogenesis and angiogenesis, consistent with a process causing airway remodelling in the absence of inflammation.
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Campbell, Gaynor Anne. "In vitro investigations of transforming growth factor-β2 induced airway wall remodelling." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/in-vitro-investigations-of-transforming-growth-factor2-induced-airway-wall-remodelling(788cb4e3-e92d-419f-bef2-ebd01887eb8b).html.
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Airway wall remodelling contributes to decreased lung function in asthma. Key features of the remodelling process are thickening of the reticular basement membrane, differentiation of fibroblast-like cells with contractile properties termed myofibroblasts and sub-epithelial deposition of extracellular matrix. The pro-fibrogenic cytokine transforming growth factor-β2 (TGF-β2) is purported to drive remodelling responses. TGF-β2 may be upregulated in asthmatic epithelium, and is secreted by bronchial epithelial cells following injury. In this study significant increases in reticular basement membrane thickening and myofibroblast differentiation were identified by histology and immunohistochemistry of mild asthmatic and healthy human bronchial biopsy tissue, although no significant differences in TGF-β2 expression were identified. It was hypothesised that the proteolytic action of house dust mite (HDM) allergens would lead to increased activation of latent TGF-β2 secreted by bronchial epithelial cells. A transformed cell line, 16HBE14o-, did not show increased activation or expression following HDM extract challenge, however TGF-β2 activation and expression was increased following exposure of primary human bronchial epithelial cells to a HDM extract. Myofibroblast differentiation and matrix deposition by healthy and mild asthmatic- derived primary bronchial fibroblasts were assessed by α-smooth muscle actin expression and soluble collagen production, following challenge with exogenous TGF-β2. Results presented here show asthmatic bronchial fibroblasts are more sensitive to the myofibroblast priming effects of TGF-β2. Bronchial epithelial cell conditioned media challenge of healthy fibroblasts led to greater increases in matrix deposition and myofibroblast differentiation than was attributable to TGF-β2, with greatest increases seen following asthmatic epithelial cell conditioned media exposure. Responses were greater than suggested by the epithelial TGF-β2 levels, so it is suggested that additional soluble mediators play a part in airway wall remodelling responses. Further work is required to identify the soluble mediators secreted by bronchial epithelial cells that control the responses of the underlying fibroblasts.
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Lai, Dilys. "Modulation of airway smooth muscle secretory responses by components of airway wall extracellular matrix : relevance to remodelling in asthma." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411028.
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McMillan, Sarah Jane. "Allergen-induced airway remodelling : investigating the role of Th2 cells and matrix metalloproteinases." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415191.
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Labram, Briony. "Defining the molecular and cellular mechanisms regulating Aspergillus fumigatus regulated airway wall remodelling in asthma." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/defining-the-molecular-and-cellular-mechanisms-regulating-aspergillus-fumigatus-regulated-airway-wall-remodelling-in-asthma(2f97458e-c053-464f-8a97-cd10cceea187).html.
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Asthma is a common chronic inflammatory condition which affects over 300 million people worldwide. Thickening of the subepithelial layer is a key feature of asthmatic airways and the extent of thickening has been correlated with severity of asthma and increased exacerbations. Recent epidemiological studies have shown a link between fungal sensitisation primarily with Aspergillus fumigatus (A. fumigatus) and exacerbations of asthma leading to increased morbidity and mortality. The airway epithelium acts as an initial defence barrier to inhaled allergens such as A. fumigatus and emerging evidence suggests that as well as orchestrating an allergic immune response, it initiates aspects of airway wall remodelling including subepithelial thickening. However, induction of a profibrogenic response by the airway epithelium following exposure to inhaled fungi associated with severe asthma has not been well documented. The epithelial expression and production of the profibrotic growth factors, TGF-β1, TGF-β2, IL-6, endothelin-1 and periostin, selected as implicated in the aetiology of asthma and their profibrotic activity, were investigated in response to both A. fumigatus spores and culture filtrate in vitro. Furthermore, in vivo chronic inhalation models using either live spores or culture filtrate from two different strains of A. fumigatus (AF293 and CEA10) were used to determine the ability of the fungi to induce murine airway wall remodelling. In vitro, spores from both strains were able to induce the expression and production of IL-6 and endothelin-1 from human bronchial epithelial cells but none of the other profibrotic growth factors. In vivo, despite spores from both strains inducing expression and production of IL-6 and endothelin-1, only CEA10 spores caused significant subepithelial collagen deposition however, both strains induced α-SMA, a myofibroblast and smooth muscle marker around the airways. As a secreted factor was suspected of driving airway wall remodelling, subsequent studies used culture filtrate produced by the two strains, AF293, a low and CEA10, a high protease producer in basal medium. Only AF293 culture filtrate induced IL-6 and endothelin-1 from human bronchial epithelial cells in vitro. However, in vivo, culture filtrate from both strains was able to induce IL-6 and endothelin-1 expression, with AF293 causing a more profound subepithelial collagen deposition and significantly increased α-SMA abundance. It was hypothesised that epithelial-derived endothelin-1 drives airway wall remodelling and hence Endothelin receptor A was inhibited in the in vivo culture filtrate inhalation model. A significant reduction in subepithelial collagen deposition and α-SMA localisation around the airways was demonstrated in mice receiving an Endothelin receptor A antagonist compared with culture filtrate alone. This thesis indicates that A. fumigatus exposure can drive features of airway wall remodelling such as subepithelial fibrosis possibly through the epithelial production of profibrotic growth factor, endothelin-1.
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Kariyawasam, Harsha Hemantha. "Airway remodelling and transforming growth factor (TGF)-β superfamily signalling in allergen-induced asthma." Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/8641.
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Bronchial biopsies obtained at baseline, 24 hours and 7 days after allergen challenge from mild atopic asthmatics were evaluated to follow the initiation and resolution of allergen-induced inflammation and remodelling in relation to AHR. Further, the expression patterns of the TGF-β Superfamily ligands (TGF-β₁₋₃, activin-A, BMP-2, BMP-4 and BMP-7) and their respective signalling pathway Type II receptors, Type I receptors and signalling Smad proteins were defined in baseline asthma and after allergen provocation in comparision with normal volunteers.
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Karuyawasan, Harsha Hemantha. "Airway remodelling and transforming growth factor (TGF)-B superfamily signalling in allergen-induced asthma." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497534.
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Berair, Rachid. "Airway structural remodelling in asthma : functional relevance and suitability as a target for therapy." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/41264.
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Airway remodelling (AR) in asthma, a collective term describing all the airway microscopic structural changes, has long been known; however, its functional relevance is poorly understood. The lack of non-invasive methods for assessing AR contributes to this scarcity of studies on AR. First, this thesis describes the association of AR with physiological markers of airflow obstruction. This was coupled with attempting to assess the link between proximal and small airway qualitative computed tomography (QCT)-derived markers and AR. Furthermore, to further study the relevance of AR, we describe the effects of fevipiprant, a novel prostaglandin D2 (PGD2) receptor 2 (DP2) antagonist, and bronchial thermoplasty (BT) on various asthma domains including AR. We found that airway smooth muscle (ASM) mass and airway vascularity was closely related to airflow obstruction. Additionally, we have demonstrated that ASM, vascularity and epithelial thickness was associated with QCT-measured proximal airway morphometry changes whereas increased vascularity and goblet cells hyperplasia was related to air trapping. Coupled with improvements is eosinophilic inflammation, asthma symptoms and lung function, we have shown that DP2 antagonism in a randomised controlled trial, resulted in improvement in epithelial integrity and reduction of ASM. Finally, we have shown that while BT treatment did not affect ASM mass, subepithelial fibrosis or lung function, it did improve epithelial integrity and reduced smooth muscle actin expression. Whether these changes contribute to the benefits seen in BT studies needs further research. This thesis has contributed to the development of fevipiprant as a new treatment for asthma, validated methods to assess AR, demonstrated how AR relates to asthma outcomes and shown how fevipiprant and BT impact AR. Further longitudinal studies are also needed to explore the heterogeneity of AR in various asthma phenotypes especially in the context of clinical trials of new therapies using novel non-invasive methods of measuring AR.
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Salmon, Michael. "Mechanisms of airway cell proliferation and pulmonary inflammation induced by ozone and allergen in Brown-Norway rats." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313031.
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Tam, Anthony. "The impact of female sex hormones on cigarette smoke-induced airway remodelling and mucus production." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/55846.
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Adjusting for amount of smoking, women have a 50% increased risk of COPD compared with men. It is not known what the anatomic basis/mechanism(s) of these sex-related differences in COPD might be. The main objective of this study is to characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodelling and emphysema in a murine model of COPD. We showed here for the first time that smoke-induced COPD in female compared to male mice have increased small airway remodelling, and may be biologically driven by estrogen through down-regulation of antioxidant defences and activation of TGFβ1 signalling, resulting in increased expression of collagen matrix in the airway walls. These effects can be ameliorated by ovariectomy before smoke exposure or use of the estrogen antagonist, tamoxifen, during smoke exposure, suggesting that estrogen is involved in this process.
Using the flexiVent system to assess the functional relationship with the observed structural changes, we showed evidence of cigarette smoke-induced lung abnormalities. Tissue damping (G), and complex input resistance of the respiratory system (Zrs) at low oscillating frequency were elevated in female compared to male mice after smoke exposure, and this effect was attenuated after ovariectomy. Quasistatic pressure-volume curve revealed a decrease in inspiratory capacity in female mice but not in male mice after smoke exposure, and this effect was attenuated after ovariectomy. Chronic smoke exposure did not increase goblet cell expression in the distal airways of all groups, suggesting that the increase in distal airway resistance in smoke-exposed female mice is unlikely to be derived from luminal exudates.
Finally, using a human bronchial epithelial cell culture model in air liquid interface, we showed that transfection with nuclear factor of activated T-cell (NFAT)c1 or NFATc2 siRNA blunted estrogen or progesterone-induced increase in MUC5AC mRNA expression, respectively.
Collectively, our data showed that estrogen may be involved in the excess risk for small airways disease in a mouse model of COPD, and MUC5AC expression is regulated by estrogen and progesterone via NFATc1 and NFATc2 in normal human bronchial epithelial cells.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Moir, Lyn Margaret. "Airway wall structural remodelling : studies on smooth muscle phemotype and contractility in isolated small bronchioles." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405168.
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Gribben, Elaine. "The role of glycosaminoglycans in neprilysin regulation and the remodelling of tissues in the airway." Thesis, Glasgow Caledonian University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.688253.
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Hossain, Mohammed Imran. "Chlamydia pneumoniae infection of Dentritic cells and its role in asthma exacerbations." Thesis, Queensland University of Technology, 2014. https://eprints.qut.edu.au/70453/3/Mohammed_Hossain_Thesis.pdf.
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Chlamydia infections are associated with exacerbations of asthma however the mechanisms are poorly understood. In this thesis we infected dendritic cells from healthy controls and asthmatic patients to determine if the immune response to chlamydial infection by these key immune cells could explain this association of chlamydial infection with asthma attacks. Infected dendritic cells from asthmatic patients showed increased expression of multiple inflammatory cytokine genes and genes for several tissue remodelling proteins, suggesting that infected dendritic cells play a central role in driving the airways damage associated with asthma. The findings provide a greater understanding of the role of infections in asthma and may provide a basis for new therapies to treat this important disease.
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Cunningham, Jason Owen. "Variation in airway remodelling genes and their role on asthma severity in children and young adults." Thesis, University of Sussex, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590080.
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Background: Asthma affects approximately 300 million people worldwide ', 5.2 million of these people live in the UK2, 1.1 million of these are children" Asthma is one of the most common chronic diseases and is the fourth leading cause of morbidity worldwide, and there is no indication of a decline in prevalence. It is hypothesised that a range of gene- environmental interactions may influence the susceptibility, severity and medication response of asthma in children and young adults". Methods: To explore these issues, two studies have been established to create datasets that will describe the phenotypic and genotypic characteristics of children with asthma in the paediatric population across Sussex and Scotland. This thesis is the output of doctoral research using data from these studies (BREATHE and PAGES) that aims to explore the interactions between variants of six genes implicated in airway remodelling and relevant environmental factors and their influence on the severity of asthma in children and young adults. This thesis is divided by analysis of individual variants. The thesis included one variant of Chitinase 3-Like-1, two variants of Matrix metalloproteinase 9, two variants of Matrix metalloproteinase 12, one variant of Matrix metalloproteinase 9, one variant of Glutathione S-tronsferase mu-1, one variant of Glutathione S-transferase theta-1 and one variant of Glutathione S-transferase pi-1. A total of eight variants were investigated. Variants were analysed for effect on multiple proxy measures of asthma severity, including asthma exacerbations, asthma treatment steps, pulmonary function and quality of life. Variants were also analysed for their effect on allergy.
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Alrifai, Mohammed [Verfasser], and Holger [Akademischer Betreuer] Garn. "Resolution of airway remodelling in a mouse model of chronic allergic asthma / Mohammed Alrifai ; Betreuer: Holger Garn." Marburg : Philipps-Universität Marburg, 2019. http://d-nb.info/1183909020/34.
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Hartley, Ruth Angela. "Using quantitative computed tomography to provide important and novel insights into airway remodelling in asthma and COPD." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/39959.
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Over the past 20 years, the technology behind Computed Tomography (CT) scan acquisition and image analysis has improved dramatically. The potential for CT to be a non-invasive method to probe the lungs has long been recognised, but there remain large gaps in our knowledge of how changes in airway structure influences airway physiology and clinical outcomes. In this thesis I examine quantitative CT (QCT) measures of airway remodelling between asthma, COPD and healthy controls, its relationship with immunohistology and its application in stratified medicine intervention studies. First I present one of the largest studies to date comparing QCT parameters in asthma, COPD and healthy controls. It confirms the heterogeneity within both diseases. However there are still distinct structural differences observed within each cohort, with striking differences seen within and between the cohorts when grouped by airflow limitation. I then present one of the largest studies to date looking at QCT measures and bronchial biopsies. This shows that changes seen on QCT correlate with typical remodelling parameters such as percentage airway smooth muscle, but not markers of inflammation. It also shows that the QCT marker of air trapping is associated with increased vascularity. Finally I present a study looking at the use of QCT in assessing the effects of a new drug, fevipiprant, aimed at reducing sputum eosinophilia, over a 12 week course. This study shows that fevipiprant, improves some clinical outcomes such as spirometry and reduces sputum eosinophilia, but no structural changes are seen on QCT.
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Naveed, Shams-un-nisa. "Matrix metalloproteinase-1 mediated extra-cellular matrix remodelling contributes to airway smooth muscle growth and asthma severity." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50577/.
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Introduction Airway remodelling describes the histopathological changes in tissue architecture observed in obstructive lung diseases such as asthma and may have a negative impact on lung function. These changes do not appear to be treated by current asthma treatments. Changes observed during airway remodelling include increased thickness of airway smooth muscle (ASM) layer and enhanced extracellular matrix (ECM) deposition. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, which facilitate tissue remodelling via ECM protein degradation. Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of patients with asthma (but not in healthy people). MMPs expression is highly regulated in lungs and is increased in disease states. My project aimed to assess MMP-1, -2 and -9 expression and activity in asthma airways. Furthermore, the underlying mechanism of MMP-1 activation and subsequently its role in airway remodelling and worsening asthma severity was investigated in the context of asthma exacerbation, which is thought to be an exaggerated lower airway inflammatory response to an environmental exposure such as respiratory virus infection. Methods Patients with stable asthma and healthy controls underwent spirometry, methacholine airway (PC20 ) challenge, exhaled nitric oxide (FeNO) test, bronchoscopy/bronchial washings and primary airway smooth muscle (ASM) cell cultures. A second asthma group (mild to moderate severity) and controls had symptom scores, spirometry and bronchoalveolar lavage (BAL) before and after rhinovirus inoculation. ECM was prepared from decellularised primary ASM cultures. MMP-1 protein levels and activity were assessed in bronchial fluid samples by enzyme-linked immunosorbent assay (ELISA), western blotting and fluorescent activity assay. ASM cell growth was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) reduction assay and cell counts. Bronchial fluid gelatinase (MMP-2 and -9) expression and activity was assessed by gelatin zymography. Results MMP-1 and MMP-9 expression was enhanced in both stable asthma and during asthma exacerbations, whilst MMP-2 expression was only increased during asthma exacerbations. MMP-1 can be activated by tryptase, which is an inflammatory product of mast cell degranulation. Activated (degranulated) mast cells enhanced proliferation of both control and asthma ASM cells via the production of a pro-proliferative ECM in vitro and the proliferative effect was dependent on MMP-1. In patients with asthma, mast cells numbers within ASM bundles were associated with ASM growth. MMP-1 protein levels were related to bronchial reactivity and MMP-1 activity increased during asthma exacerbations, where its levels were related to exacerbation severity. Conclusion This study suggests that MMP-1 plays an important role in asthma pathophysiology and that ASM/mast cell interactions contribute to asthma severity by transiently increasing MMP-1 activation, ASM growth and airway responsiveness. Moreover, there is increased expression of MMP-2 and -9 during asthma exacerbations compared with stable asthma. As both MMP-2 and -9 act as mediators of inflammation (Okada, S. et al., 1997) (Elkington, P.T.G., 2006) and tissue remodelling (Oshita, Y. et al., 2003), an increase in gelatinolytic activity linked to MMP-2 and MMP-9 is also likely to play a significant role in the pathophysiology of asthma exacerbations.
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Prabhala, Pavan. "The impact of precise MKP-1 regulation and modulation on cytokine expression in asthma and airway remodelling." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/14954.
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Asthma is a chronic inflammatory disease characterised by airway obstruction, hyperresponsiveness and remodelling. Cytokines drive many inflammatory diseases and change the balance of inflammatory and anti-inflammatory molecules along the underlying molecular pathways. Hence targeting the molecular mechanisms responsible for cytokine secretion allows us to develop novel strategies to repress inflammation. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study we investigate the p38 MAPK-mediated anti-inflammatory molecule; mitogen-activated protein kinase phosphatase 1 (MKP-1). MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally-distinct manner, MKP-1 is able to repress cytokine expression, via the action of another anti-inflammatory molecule; tristetraprolin (TTP). The structure of MKP-1 can be manipulated at the level of transcription and translation. We specifically focused on the post-translational changes to increase its longevity and possibly its activity. This was achieved through the use of inhaled corticosteroids and by altering the proteasome-MKP-1 binding domain. Utilizing primary cultures of airway smooth muscle cells in vitro we explored the temporal regulation of IL-6 cytokine expression upon stimulation with tumor necrosis factor (TNF). IL-6 cytokine expression was then used as a model to explore the interaction between p38 MAPK induced anti-inflammatory molecules MKP-1 and TTP. We show that cytokine expression in ASM cells is p38 MAPK-dependent and that the anti-inflammatory regulatory network is also controlled by p38 MAPK-mediated phosphorylation. We also show that the balance of this regulatory network can be altered in the presence of dexamethasone or compounds that interrupt the proteasomal binding of MKP-1. Together, p38 MAPK, MKP-1 and TTP may form a regulatory network that exerts significant control on cytokine secretion, which can then be altered.
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Brodlie, Malcolm James. "Development of a primary airway epithelial cell culture model and explanted tissue archive to study the role of neutrophilic inflammation and airway remodelling in cystic fibrosis lung disease." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1228.
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Cystic fibrosis (CF) is the most common inherited life-limiting condition in the United Kingdom. Lung disease, involving retention of mucopurulent secretions, neutrophilic inflammation and endobronchial infection is the major cause of mortality. CF is caused by variants in the CF-transmembrane conductance regulator gene, however the exact pathogenesis of lung disease is not fully understood. Valid experimental models are therefore critical to advance research. I describe the establishment of a successful method to culture primary bronchial epithelial cells (PBECs) from explanted CF lungs removed at transplantation. This technique has yielded an important resource to further study the pathogenesis of CF lung disease. The cytokine interleukin-17 orchestrates the activity of neutrophils and increases mucin gene expression in BECs – two key features of CF lung disease. I demonstrate that interleukin-17 is increased in the airway of people with advanced CF lung disease. I also show evidence suggesting that neutrophils themselves may be a source of interleukin-17 potentially leading to an ever-increasing spiral of inflammation. In a CF mouse model ceramide accumulates in BECs and is associated with neutrophilic inflammation and susceptibility to Pseudomonas aeruginosa infection. Furthermore, amitriptyline treatment normalised ceramide, inflammation and susceptibility to infection. The role of ceramide is a complex area, however, with a divergence of opinion in the literature and paucity of human data. I demonstrate using immunohistochemistry that ceramide is increased in the lower airway epithelium in advanced CF lung disease compared to pulmonary hypertension and unused lung donors and is correlated with neutrophilic inflammation and increased in those colonised with Pseudomonas aeruginosa. Ceramide species C16:0, C18:0 and C20:0 but not C22:0 are increased in lung homogenates of CF lungs compared to pulmonary hypertension measured using the independent technique of high performance liquid chromatographymass spectrometry. Both interleukin-17 and ceramide represent important topics for further translational CF lung disease research.
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Nath, Puneeta. "Investigation of T-helper type 2 cytokines and the mitogen-activated protein kinase pathway in the modulation of bronchial hyperresponsiveness, airway inflammation and remodelling." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417857.
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Salgado, Daniel Cauduro. "Distribuição de colágeno na concha nasal inferior de pacientes com rinite alérgica ou idiopática." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5143/tde-12012015-104722/.
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INTRODUÇÃO: Embora seja reconhecida a existência do espessamento da membrana basal e da fibrose da concha nasal na rinite alérgica, não há estudos descritivos do comportamento da mucosa nasal nos pacientes com rinite idiopática. O propósito desse estudo é descrever possíveis alterações na membrana basal e na lâmina própria da concha nasal inferior em pacientes com rinite alérgica ou idiopática, além do estudo quantitativo das fibras colágenas nesta localização. MÉTODOS: Analisou-se na concha nasal inferior obtida através de turbinectomia bilateral em 28 pacientes - 14 com rinite alérgica e 14 com rinite idiopática - a área ocupada pelo colágeno, a espessura da membrana basal e o diâmetro das fibrilas de colágeno através do uso de microscopia óptica (coloração Hematoxilina-eosina e Picrossírius-hematoxilina), microscopia eletrônica e imunoistoquímica para laminina e colágeno IV. RESULTADOS: 1) pacientes com rinite alérgica apresentaram significantemente maior área da concha nasal ocupada por colágeno do que o grupo com rinite idiopática. 2) a membrana basal de pacientes com rinite alérgica foi significantemente mais espessa. 3) a lâmina reticular da membrana basal dos pacientes com rinite alérgica apresentaram fibrilas de colágeno com menor diâmetro que os pacientes com rinite idiopática. 4) não houve diferenças significativas entre os grupos na distribuição de laminina e de colágeno IV. CONCLUSÕES: Alterações na mucosa nasal ocorrem na rinite alérgica, sendo caracterizadas pelo aumento da espessura da membrana basal e por fibrose. Na rinite idiopática, observou-se uma mucosa com aspecto estrutural semelhante aos pacientes normaisINTRODUCTION: Despite our knowledge about nasal conchae fibrosis and basement membrane thickening in allergic rhinitis, there are no descriptive studies on nasal mucosa behavior in patients with idiopathic rhinitis. The aim of our study was to describe possible changes in the basement membrane and lamina propria of the inferior concha in patients with idiopathic or allergic rhinitis, in addition to a quantitative study of collagen fibers in this site. METHODS: The inferior nasal concha obtained from 28 patients submitted to bilateral turbinectomy was examined - 14 with allergic rhinitis and 14 with idiopathic rhinitis; analyzing the collagen area, the basement membrane thickness and the collagen fibrils diameter using optical microscopy (Hematoxylin-eosin and Picrosirius-hematoxylin staining), electron microscopy and immunohistochemistry for laminin and collagen IV. RESULTS: 1) patients with allergic rhinitis had a significantly larger area of the nasal concha occupied by collagen than the group with idiopathic rhinitis. 2) the basement membrane of patients with allergic rhinitis was significantly thicker. 3) the reticular lamina of the basement membrane of patients with allergic rhinitis had collagen fibrils with diameters which were smaller than those from patients with idiopathic rhinitis. 4) there were no significant differences between the groups concerning the distribution of laminin and collagen IV. CONCLUSIONS: Alterations to the nasal mucosa that happen in allergic rhinitis are characterized by basement membrane thickening and fibrosis. In idiopathic rhinitis the patients\' mucosae were structurally similar to those from normal patients
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Lederlin, Mathieu. "Etude de l’atténuation scanographique de la paroi bronchique dans l’imagerie de l’inflammation et du remodelage des voies aériennes." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21905.
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L’inflammation et le remodelage des voies aériennes sont des processus pathologiques de signification pronostique différente qui caractérisent la plupart des maladies obstructives bronchiques, asthme et bronchopneumopathie chronique obstructive (BPCO) notamment. L’examen histologique de l’inflammation et du remodelage requiert un geste biopsique invasif qui est rarement réalisé en routine. Le développement de méthodes d’évaluation non invasives autoriserait un phénotypage plus précis des patients et le développement de thérapeutiques ciblées. Les progrès de la tomodensitométrie (TDM) ont favorisé l’essor d’une imagerie quantitative permettant des mesures morphométriques des lumières et parois bronchiques. Ces paramètres morphométriques sont corrélés aux indices fonctionnels d’obstruction mais leur manque de standardisation limite leur utilisation en routine. Nous avons étudié chez l’homme et le petit animal des paramètres TDM basés non pas sur la morphométrie mais sur la densitométrie de la paroi bronchique. Nos résultats dans l’asthme et la BPCO indiquent que l’atténuation pariétale bronchique possède une valeur diagnostique au moins équivalente à celle des paramètres morphométriques, est mieux corrélée aux indices d’obstruction fonctionnelle, et pourrait être un marqueur du remodelage dans l’asthme. Chez la souris asthmatique, les paramètres d’atténuation péribronchique extraits d’image de micro-TDM sont aussi corrélés au remodelage histologique. Le concept d’atténuation pariétale bronchique est donc prometteur pour l’étude non invasive du remodelage même si des étapes supplémentaires de validation sont nécessaires pour s’assurer de la reproductibilité des méthodesAsthma and chronic obstructive pulmonary disease (COPD) are frequent conditions characterized by two main pathological changes: bronchial inflammation and remodelling. Pathological examination requires invasive biopsy, which is rarely performed in routine. Therefore there is a great interest in developing non-invasive methods that would lead to more precise phenotyping of patients and the development of new targeted treatments. Computed tomography (CT) can provide a quantitative morphometry-based analysis of the airways. These morphometric parameters have been shown to correlate with functional obstruction but are poorly used in routine practice due to their lack of standardisation. The aim of our studies was to investigate the value of CT attenuation-based parameters in humans and animals. In asthma and COPD, we have shown that the wall attenuation value had diagnostic performances comparable to those of morphometric parameters, correlated better with functional obstructive indexes, and could be a marker of remodelling in asthma. In asthmatic mice, peribronchial attenuation values extracted from respiratory-gated micro-CT images correlate with remodeling. Therefore, the concept of bronchial wall attenuation seems to be promising for assessing non-invasively airways remodeling. Further studies are required to ensure the full reproducibility of these methods
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Abdelsadik, Ahmed Mohammed Khalil [Verfasser]. "Hypoxia induces processes related to inflammation and remodelling in the airways of the fruit fly Drosophila melanogaster / Ahmed Mohammed Khalil Abdelsadik." Kiel : Universitätsbibliothek Kiel, 2012. http://d-nb.info/1021342610/34.
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Eapen, MS. "Understanding cellular changes and mediators of airway remodelling in COPD." Thesis, 2018. https://eprints.utas.edu.au/28492/1/Eapen_whole_thesis.pdf.
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\(Background\) \(and\) \(Aims:\) Chronic obstructive pulmonary disease (COPD) is emerging as a substantial global health problem, with an estimated annual mortality of over 3 million people, which is the third largest disease cause worldwide. COPD is an irreversible chronic, slowly progressive airway obstructive respiratory disease. Cigarette smoking mainly causes it, primarily through small airway fibrosis, narrowing and ultimately obliteration, accompanied by more generalized but non-obstructive “chronic bronchitis” throughout the airways, and in some individuals complicated by the later development of lung parenchymal destruction (emphysema). Approximately 50% of smokers develop COPD eventually.
In COPD research, there has been a long-held belief that airway disease progression is due to “inflammation.” Although this may be true in the airway lumen with innate immunity activated by the effect of smoke or secondary to infection, the accurate picture for inflammatory cells in the airway wall, where the pathophysiological COPD remodeling occurs, is uncertain and especially so in mild to moderate COPD patient’s, i.e., earlier disease. This study follows up on a previous finding from our group of possibly decreased cellularity in the airway wall of patients with COPD. Thus, in the current studies, along with total airway wall cellularity, I evaluated the contribution of the main immune cells such as neutrophils, macrophages, mast cells, CD4 and CD8 cells in the large and small airway wall of mild-moderate COPD current (CS) and ex-smokers (ES), plus normal lung function smokers (NLFS), and compared them to non-smoker controls (NC). My studies further delved into the macrophage sub-populations in smokers/COPD and ascertained whether abnormal differential switching occurs in the macrophage population in the small airway wall compared to the lumen. I also measured macrophage-related cytokine profiles in airway luminal bronchoalveolar lavage fluid (BALF) and investigated whether the microenvironment dictated these changes. I evaluated cell dysfunction in small airway wall cells by assessing their degranulating potential via expression of a degranulating-marker lysosome-associated membrane protein -1 (LAMP-1). While analyzing the CD68+ population of macrophages, I noticed that many cells staining strongly were not macrophages as expected, but spindle-shaped cells likely to be a population of fibroblasts; indeed the literature strongly suggests that CD68 can also stain fibroblasts, but this has until now been ignored in respiratory research.
I further focused on the non-inflammatory cell components in the airway wall, investigated the relationship between alpha-smooth muscle actin+ myofibroblasts with an expression of epithelial-mesenchymal transition markers (a focus of our group for several years), key extracellular matrix proteins (collagen I and fibronectin) and airway wall thickness. I also related abnormalities to lung function disturbance in COPD.
In the final phase of my Ph.D. studies, I also managed to complete some preliminary investigations on abnormal lysosomal accumulation and catabolic changes in the airway epithelium of COPD patients and related these to indices of airway remodeling.
\(Methodology:\) I evaluated both large airway endobronchial biopsies (ebb) and small airway lung resected tissues (RT) from COPD-CS and ES, NLFS and NC. I immune-stained with human anti-CD68+ for macrophages, neutrophil elastase for neutrophils, mast cell tryptase for mast cells, CD4+ and CD8+ for T cell populations. I conducted total cell counts as well as differential counts in the airway wall lamina propria (LP), epithelium and reticular basement membrane. For the large airways, I standardized cell counts in the LP by taking the depth of 150 for LA and up to 100 microns deep SA while excluding smooth muscle layers. Further, subpopulations of macrophages were evaluated in the SA wall (epithelium and LP) and BAL samples from the same cohort of patients and were stained with CD163 and Arginase-1 antibodies for detection of M2 macrophages and dual stained with anti-CD68+ and anti-iNOS antibodies for M1 populations (CD68+ only cells were designated M0). Cells were quantified and normalized as per mm2 of SA wall and as per mm of length for the epithelium, respectively. Bronchoalveolar lavage (BAL) cytospin macrophages were similarly stained and enumerated by randomly selecting 12 fields and quantified as per ml of original BAL fluid extracted. BAL cytokines to profile for both M1/Th1 and M2/Th2 cytokines used FACS multiplexing strategies.
The degranulation capacity of mast cells and total degranulating cells in the small airway wall were measured by dual staining mast cells with anti-mast cell tryptase and LAMP-1. Epithelial and sub-epithelial LAMP-1 were assessed per area and represented as percent degranulation. I measured the total airway wall thickness of SA and divided it into the epithelium, reticular basement membrane (Rbm) LP, smooth muscle layer, and sub-mucosal adventitia, which meets the alveolar tissue. Further, I quantitated the α-SMA+ cells present in the SA lamina propria and adventitia, while the ECM markers (collagen-1 and fibronectin) were quantitated as a percentage of area staining in the same areas.
\(Results:\) I confirmed hypo-cellularity in the airway wall in both large and small airways in smokers and in COPD; with LA wall cellularity least in the COPD-current smoker (CS), while SA cellularity was similar across smoker/COPD groups. LA neutrophils were decreased in COPD-CS, while SA neutrophil counts were unchanged. In contrast, a small but significant increase was observed in SA CD8+ cells in both normal smokers and COPD-CS but not in LA. Ratiometric analysis of CD4+ and CD8+ T cells showed a dominance of the CD8+ phenotype in the LP area of LA, but not SA. Compared to controls, LA macrophage numbers in COPD were significantly lower, with SA macrophage numbers unchanged. Further evaluation of the SA macrophage subpopulations showed a significant increase in pro-inflammatory M1s in the small airway walls of NLFS and COPD compared to controls with a reciprocal decrease in M2 macrophages, which remained unchanged among pathological groups. However, luminal macrophages went the other way, with a dominant M2 phenotype in both NLFS and COPD subjects. BAL cytokine profiles were skewed towards M2 with an increase in CCL22, IL-4, IL-13, and IL-10 in both NLFS and COPD.
A decrease in degranulating mast cell and total degranulating cells was observed in the SA wall via monitoring intracellular LAMP-1 expression. Further, and unexpectedly, this lysosomal LAMP-1 expression was also found to be markedly increased in the epithelium of small airways in COPD. This increase in LAMP-1+ lysosomes significantly correlated with a decrease in lung function increased airway obstruction and increased in airway thickness.
Among the non-inflammatory cell populations characterized, I found a significant and marked increase in αSMA+ myofibroblast numbers in the small airway tissue in both smokers and COPD compared to normal controls, which directly correlated with decreased airway caliber measures in COPD patients. A significant increase was observed in the ECM proteins collagen-1 and fibronectin in the small airway wall of smoker and COPD groups. The proliferation of myofibroblast directly co-related to this increased collagen and fibronectin deposition and airway wall thickening, which suggested an active role in airway remodeling. The increase in the myofibroblast population also correlated with increases in expression of the EMT markers S100A4 and vimentin and lung function.
\(Conclusions:\) These current studies confirmed our group`s novel finding of hypocellularity in the airway wall of COPD patients, both in large and small airways. Analysis of the literature suggests that this has hardly been looked previously and probably not as rigorously as this investigation. These changes corresponded to decreases in most airway inflammatory and immune cells. Overall, the contribution of inflammatory/immune cells to total airway wall cells was small, again something else never previously documented, with the majority likely to be stromal cells. Macrophage subpopulation showed abnormal differential switching in both the airway wall and lumen, though in different directions. Lack of degranulation activity in the cells of the airway wall in COPD indicated dysfunctionality, which could be crucial in viral and bacterial infections known to be essential disease exacerbations in particular. A proliferation of myofibroblast was present in small airways and strongly associated with both remodelling, active EMT and loss of airflow in COPD.
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Soltani, Abhari A. "Airway remodelling in smokers with or without chronic obstructive pulmonary disease (COPD) and the effects of inhaled corticosteroids on remodelling in COPD." Thesis, 2010. https://eprints.utas.edu.au/10766/1/Amir_Soltani_whole%20_thesis.pdf.
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`Introduction:` Smoking-related COPD is a worldwide health problem. Airway remodelling is defined as structural changes occurring in chronic inflammatory diseases of the airways. Our knowledge about airway remodelling in COPD is very limited. My preliminary observational study of bronchial biopsies (BB) from COPD subjects revealed reticular basement membrane (Rbm) fragmentation and vascular changes. I hypothesised that these changes are specific for COPD and are related to the angiogenic activity of vascular endothelial growth factor (VEGF) and transforming growth factor-ß (TGF-ß). I also aimed to study the effects of inhaled corticosteroids (ICS) on these airway changes.
`Methods:` A cross-sectional study compared BB from current smokers with COPD (SCOPD), ex-smokers with COPD (ES-COPD), current smokers with normal lung function (S-N) and healthy nonsmoking (H-N) subjects. BB were stained with anti-Collagen IV, anti-VEGF and anti-TGF- ß antibodies. Rbm fragmentation and vessels in the Rbm and lamina propria (LP) were measured. Anti-Factor VIII antibody was compared with anti-Collagen IV antibody in detecting vessels. Then a double-blind, randomized and placebo controlled study assessed the effects of ICS on airway remodeling, VEGF and TGF- ß in COPD.
\(Results:\) Airway remodelling changes were also detectable in S-N. The Rbm was fragmented. The length of splits was significantly greater in both COPD groups and in S-N than controls (p<0.02). The Rbm was hypervascular and the LP hypovascular in current smokers compared with controls (p<0.05). Vessels stained for VEGF and TGF-ß were increased in the Rbm of both COPD groups and S-N (p<0.05). Factor VIII antibody confirmed my finding of hypovascularity of the LP in S-COPD. ICS reversed Rbm splitting but did not have any effect on vessel remodelling and angiogenic activities.
`Discussion:` My studies revealed novel aspects of Rbm and vascular remodelling in BB from COPD subjects and S-N and for the first time showed that ICS are effective on Rbm changes in COPD. Rbm fragmentation, we think, is probably a consequence of the effects of proteolytic enzymes on the Rbm due to activation of epithelial-mesenchymal transition (EMT) by smoking. This is under more investigation in our group. My study could not explain the mechanisms to vessel changes in current smokers. Further studies to examine the role of other angiogenic/antiangiogenic factors are now needed. Absence of vascular changes in ES-COPD subjects may imply that vascular remodelling is reversible with smoking cessation, but to test this we need a longitudinal smoking cessation study.
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Sohal, SS. "Epithelial activation in chronic obstructive pulmonary disease (COPD)." Thesis, 2010. https://eprints.utas.edu.au/10765/34/Sohal_whole%20_thesis.pdf.
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`Background:` Early on I identified that reticular basement membrane (Rbm) in current smokers with COPD was highly fragmented, with cracks termed “clefts” containing cells. This looked like the described hallmark of EMT (epithelial mesenchymal transition). I followed this preliminary observation with a comprehensive cross-sectional study in which I hypothesized that the airway epithelium is activated in smokers, and that this may promote EMT, but that this will be especially active in COPD. As a part of my thesis, I also investigated the
expression and activity of the anti-inflammatory enzyme HDAC2 (histone deacetylase 2) which is reported to be reduced in COPD lungs and may account for associated pulmonary inflammation. I hypothesised that the current literature is correct in stating that HDAC2 is down-regulated in COPD airways and also that these reduced HDAC2 levels are normalised by aggressive inhaled corticosteroid (ICS) therapy and smoking cessation in patients with COPD.
\(Methods\) \(and\) \(results:\) Endobronchial biopsies (ebb) from current smokers with COPD (COPD-CS) and ex-smokers with COPD (COPD-ES), smokers with normal lung function (NS) and never-smoking controls (NC) stained for markers of EMT, matrix metalloproteinase-9 (MMP-9), fibroblast protein (S100A4), epidermal growth factor receptor (EGFR), vimentin and cytokeratins. To confirm the extent of suppressed HDAC2 ebb were immuno-stained for HDAC2. In a double-blind, randomized, placebo-controlled study, I assessed the effects of ICS on Rbm fragmentation and HDAC2. Compared to NC, there was significant fragmentation of the Rbm in COPD-CS, COPD-ES and NS groups. COPD-CS, NS and COPD-ES demonstrated increases in staining for: basal epithelial S100A4, epithelial EGFR and MMP-9 and S100A4 for cells in Rbm ``clefts`` compared to NC. Dual staining revealed that vimentin (a mesenchymal marker) co-stained with cytokeratin (an epithelial marker). ICS normalised Rbm fragmentation. Compared to NC there was significant increase in HDAC2 positive cells in NS in the lamina propria (LP) but a decrease in COPD-CS. However, this latter abnormality was due to a reduction in total LP cells and not % cell HDAC2 staining. There were significantly more HDAC2 positive cells in COPD-ES compared to COPD-CS, but again due to an increase in total cell numbers. ICS made no difference to HDAC2 staining.
`Conclusions:` This is the first description of likely EMT in smoking and COPD. ICS reversed Rbm fragmentation. HDAC2 expression was reduced in smokers but confounded by changes in cellularity. Quitting does seem to have a real effect on upregulating HDAC2, but it is not affected by ICS.
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Haw, Tatt Jhong. "Investigation of pathogenesis of chronic obstructive pulmonary disease." Thesis, 2016. http://hdl.handle.net/1959.13/1318484.
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Research Doctorate - Doctor of Philosophy (PhD)Chronic Obstructive Pulmonary Disease (COPD) affects more than 64 million people globally and is primarily caused by cigarette smoke (CS) exposure. It is the third leading cause of morbidity and mortality worldwide and imposes significant socioeconomic burden worldwide. COPD is a chronic lung disease characterised by chronic pulmonary inflammation, airway remodelling and emphysema. These pathologies consequently culminate in progressive lung function decline and airflow limitation. Current therapies for the management of COPD are largely ineffective. They provided symptomatic relief to patients and do not target the underlying causal factors of COPD. Hence, there is a lack of effective treatments and an urgent need for research into the identification and development of therapeutic strategies in treating COPD. The lack of effective treatments is due to the poor understanding of immunological processes and mechanisms that underpin the pathogenesis of COPD. Our laboratory has recently established a murine experimental model of COPD by exposing mice to nose-only inhalation of tightly regulated dose of CS. Importantly, our CS-induced model of COPD recapitulates the hallmark features of human disease in a relatively short period of time. Thus, this allows us to investigate and examine the immunological processes and mechanisms that underpin the pathogenesis of COPD. The aims of the studies described in this thesis were to identify and elucidate immunological processes that underpin the pathogenesis of COPD. The first study identified a novel role for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting CS-induced COPD. TRAIL and its receptors were increased by CS exposure in mice and in lung samples from human COPD patients. TRAIL-deficient mice or wild-type (WT) mice treated with neutralising TRAIL monoclonal antibodies had significantly reduced CS-induced pulmonary inflammation, expression of pro-inflammatory mediators, emphysema-like alveolar enlargement and improved lung function. The second study investigated the role of Toll-like receptor (TLR)2 and TLR4 in CS-induced pathogenesis of COPD. CS-induced pulmonary inflammation was largely unaltered in the absence of TLR2 or TLR4. TLR2-deficient mice had CS-induced emphysema-like alveolar enlargement, apoptosis and impaired lung function compared to normal air-exposed mice that was equivalent to CS-exposed WT mice, whilst small airway remodelling was not altered. By contrast, TLR4-deficient mice had reduced CS-induced emphysema-like alveolar enlargement, apoptosis and impaired lung function compared to WT mice. Interestingly, CS-induced small airway fibrosis, characterised by increased collagen deposition around small airways, was ablated in TLR4-deficient mice. The third study identified a previously unrecognised role for TLR7 in the pathogenesis of COPD. In the absence of TLR7, CS-induced pulmonary inflammation was not altered compared to CS-exposed WT controls. CS-induced small airway epithelial cell thickening was reduced whilst collagen deposition increased in the absence of TLR7. Importantly, CS-induced emphysema-like alveolar enlargement and apoptosis were reduced in TLR7-deficient mice. Administration of the TLR7 agonist imiquimod synergistically increased CS-induced emphysema and apoptosis. Interestingly, imiquimod-induced emphysema and apoptosis may occur through the activity of mast cell-specific proteases, in particular mouse mast cell protease-6 (mMCP-6). Crucially, antibody-mediated neutralisation of TLR7 also reduced CS-induced emphysema and apoptosis in the lungs in experimental COPD. Our novel findings indicate that TRAIL and TLRs, in particularly TLR2, TLR4 and TLR7, have critical roles in CS-induced development of COPD. TRAIL promotes CS-induced pulmonary inflammation, emphysema-alveolar enlargement and lung function impairment. TLRs have little or minor role in CS-induced pulmonary inflammation. TLR2 may protect against CS-induced emphysema and lung function impairment, whilst TLR4 and TLR7 induce these disease features of COPD. TLR4 promotes CS-induced airway fibrosis whilst TLR2 and TLR7 regulate collagen deposition around small airways. Collectively, our studies significantly advance the understanding of the immunological mechanisms that underpin the pathogenesis of COPD and may facilitate the development of novel treatments for COPD in the future.
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Setlakwe, Emilie L. "Subepithelial collagen content in the peripheral airways of heaves-affected and control horses." Thèse, 2011. http://hdl.handle.net/1866/6886.
Full textAbstract:
Chez les patients asthmatiques, on retrouve un remodelage de la matrice extracellulaire des poumons, caractérisé par une augmentation du collagène ou fibrose de la couche sous-épithéliale des voies respiratoires. Le souffle, maladie inflammatoire chronique des voies respiratoires inférieures des chevaux matures, présente des similarités physiopathologiques avec l’asthme humain, incluant le remodelage. Ceci nous conduit à l’hypothèse que la fibrose de la couche sous-épithéliale pourrait être une composante des lésions pulmonaires chez les chevaux affectés, ce que notre étude avait pour objectif d’évaluer.
Des biopsies pulmonaires périphériques réalisées par voie thoracoscopique ont été obtenues chez 5 chevaux témoins et 6 chevaux atteints du souffle, avant (T0) et après une stimulation antigénique de 30 jours avec du foin moisi et de la paille. Avant le début de l’étude, les sujets étaient en rémission clinique et ne démontraient aucun signe clinique de maladie. Un examen microscopique des échantillons prélevés a été réalisé après traitement au picrosirius-rouge, colorant spécifique des fibres de collagène. La surface du collagène de la couche sous-épithéliale a été mesurée et corrigée en fonction de la taille de la voie respiratoire en utilisant des techniques morphométriques standards.
Les chevaux atteints de souffle ont une surface de collagène plus grande dans la couche sous-épithéliale (p<0.1) en comparaison avec les chevaux témoins. La fibrose de la couche sous-épithéliale demeure inchangée chez les chevaux malades après la stimulation antigénique de 30 jours. À T0, la fibrose de la couche sous-épithéliale est associée positivement aux variations maximales de pression pleurale et à la résistance pulmonaire chez les chevaux atteints de souffle.
Les résultats de cette étude suggèrent qu’une fibrose de la couche sous-épithéliale est présente dans les voies respiratoires périphériques des chevaux atteints de souffle et contribue au déficit de fonction résiduel pulmonaire observé lors de rémission clinique.Extracellular matrix remodelling is present in the human asthmatic lung, and is characterized by increased collagen or fibrosis of the subepithelial area of the airway. Heaves, a naturally occurring chronic lower airway inflammatory condition in horses shares aspects of pathophysiology with asthma, including features of airway remodelling. We thus hypothesize that airway fibrosis is a characteristic of remodelling in heaves. The aim of this study was to evaluate the presence of fibrosis in the subepithelial area of the peripheral airways of heaves-affected horses. Peripheral lung biopsies acquired under thoracoscopic guidance were obtained from 5 control and 6 heaves-affected horses, both before (T0) and after a 30 day antigenic challenge with mouldy hay and straw. Prior to the study, diseased horses were in clinical remission and exhibited no clinical signs of disease. Obtained samples were microscopically examined using picrosirius-red, a collagen specific histological staining technique. Collagen area in the subepithelial layer, e.g. the region between the airway smooth muscle and the epithelial layer was measured, and corrected for airway size using standard morphometric techniques. In comparison with controls, heaves-affected horses had an increased collagen content in the airway subepithelial area (p<0.1). No change in fibrosis of the subepithelial area was observed in diseased horses after the 30 day antigenic challenge. Peripheral airway subepithelial collagen at baseline was positively associated with maximal changes in transpulmonary pressure and pulmonary resistance in horses with heaves but not in controls. Results of this study indicate that fibrosis of the subepithelial area is present in the peripheral airways of heaves-affected horses, and may play a role in residual lung function deficits observed in diseased horses even while in clinical remission.
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Koucký, Václav. "Detekce časných patofyziologických změn dýchání u dětí s chronickým plicním onemocněním." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-412517.
Full textAbstract:
Detection of early pathophysiological changes of breathing in children with chronic respiratory disease MD. Vaclav Koucky - Ph.D. thesis Abstract Introduction: Currently, there are different methods for infant pulmonary function testing (iPFT) and morphological assessment of microscopic changes in endobronchial biopsy samples (EBB). In research setting, they allow detection of early pathophysiological changes of breathing in small children with chronic respiratory disease, respectively in risk of its development. Their clinical significance, however, is not fully acknowledged. The aim of this thesis is to evaluate the safety, feasibility and clinical significance of iPFT and EBB in infants younger than 2 years of age. In addition, the relationship between functional and morphological changes of respiratory tract and the function of peripheral chemoreceptors was studied in selected patients' subgroups. Methods: Fifty-five infants with cystic fibrosis (CF), 35 physician-confirmed recurrent wheezers (AB), 9 infants with congenital diaphragmatic hernia, 7 with interstitial lung disease (chILD) and 3 with primary ciliary dyskinesia (PCD) were enrolled. All infants underwent iPFT and relevant clinical history data were recorded. Based on patients' age, CF group was divided into CFmalí (< 6 months) and CFvelcí (>...