Dissertations / Theses on the topic 'Glucocorticoid resistance in Asthma'
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1
Matthews, John Graham. "The differential effects of glucocorticords in glucocorticoid-dependent asthma, glucocorticoid-resistant asthma and healthy subjects." Thesis, Imperial College London, 2006. http://hdl.handle.net/10044/1/8204.
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Lane, Stephen John. "Mechanism of glucocorticoid resistance in chronic bronchial asthma." Thesis, King's College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300513.
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Loke, Tuck-Kay. "The cellular & molecular pathology of glucocorticoid resistant asthma." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430825.
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YAMAMOTO, MASAHIRO, YUTAKA OISO, MITSUYA MORIKAWA, SATOSHI KAKIYA, HISASHI YOKOI, ATSUSHI SUZUKI, and AKITOSHI KAWAKUBO. "A CASE OF PRIMARY GLUCOCORTICOID RESISTANCE." Nagoya University School of Medicine, 1995. http://hdl.handle.net/2237/16090.
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Hinds, Terry D. Jr. "Protein Phosphatase 5 and Glucocorticoid Receptor beta in Glucocorticoid Resistance and Lipogenesis." University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1289929592.
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Jaffuel, Dany. "Corticothérapie et asthme : étude cellulaire de la transrépression du facteur de transcription AP-1 par le récepteur aux glucocorticoi͏̈des." Montpellier 1, 1997. http://www.theses.fr/1997MON11104.
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Gaffey, Kate. "Glucocorticoid resistance in COPD : the role of p38 MAPK." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/glucocorticoid-resistance-in-copd-the-role-of-p38-mapk(9c60954b-f891-4f8b-8004-825e6d173503).html.
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Chronic Obstructive Pulmonary Disease (COPD) is a chronic, inflammatory condition, characterised by airflow limitation. The use of glucocorticoids (GC) as an anti-inflammatory treatment in COPD has limited clinical benefits, and as such, new treatments are needed. Identifying key pathways involved in the inflammatory response in COPD may enable the development of novel treatments. The aims of this thesis were to examine the steroid sensitivity of an in vitro mixed sputum culture cell model, comparing COPD cells to smoking and non-smoking controls, examine expression of the intracellular signalling molecule p38 Mitogen Activated Protein Kinase (MAPK) in COPD lungs compared with controls, examine the GC and p38 MAPK inhibitor and dual therapy sensitivity of a bronchial epithelial cell line and finally, to understand the mechanisms by which a p38 MAPK inhibitor in combination with a GC synergistically inhibit pro-inflammatory mediator production in a bronchial epithelial cell line. Dexamethasone inhibits mixed sputum cell pro-inflammatory mediator release, with no differences in sensitivity observed between COPD and control cells. Isolated sputum neutrophils demonstrate modest sensitivity to dexamethasone, which is in contrast to blood neutrophils. There are increased numbers of cells positive for activated p38 MAPK in COPD lungs compared with controls, specifically localised to follicular B and CD8+ T cells, bronchial epithelial cells and alveolar and sputum macrophages. Lung and sputum neutrophils are devoid of activated p38 MAPK, and a pharmacological p38 MAPK inhibitor has no effect on pro-inflammatory mediator production from these cells. This is in contrast to blood neutrophils, whereby p38 MAPK activation can be induced following LPS stimulation and in vitro cell culture, and pro-inflammatory mediator release is inhibited by a p38 MAPK inhibitor. Dexamethasone and birb 796 inhibit stimulated pro-inflammatory mediator release from a bronchial epithelial cell line in a dose-dependent manner. Sensitivity to either drug is dependent on stimuli and the pro-inflammatory mediator analysed. There is additive and synergistic inhibition of pro-inflammatory mediator production when combination therapy comprising dexamethasone and birb 796 is used compared with either drug alone. This may be due to Birb 796 enhancing dexamethasone-mediated nuclear translocation of the glucocorticoid receptor, which may enhance the GC-mediated anti-inflammatory effects. Combination therapy may therefore be a useful therapeutic in the treatment of COPD.
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Kmyta, V. "Bcli polymorphism of glucocorticoid receptor gene in patients with bronchial asthma and obesity." Thesis, Sumy State University, 2015. http://essuir.sumdu.edu.ua/handle/123456789/40552.
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Certain investigations showed that genetic factors of
bronchial asthma (BA) and obesity overlap each other, this indicates
that they have common genetic predisposition. Thus, BA and obesity
are associated with the genes, which encode β-adrenergic receptor,
insulin-like growth factor, IL-1α, leukotriene A4 hydroxylase,
glucocorticoid receptor (GR), uncoupling protein, etc.
9
Butler, C. A. "Mechanisms of steroid resistance in therapy resistant asthma." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546017.
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Nixon, Mark. "Interactions between glucocorticoid metabolism and inflammation in obesity and insulin resistance." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5593.
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Inflammation plays a key role in the underlying pathogenesis of obesity and its associated health risks, with increased markers of inflammation evident in both liver and adipose tissue. In parallel, there is dysregulation of glucocorticoid metabolism in obesity, with increased adipose levels of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and increased hepatic levels of 5α-reductase type 1 (5αR1), which catalyses the reduction of glucocorticoids. Both the mechanisms and consequences of this glucocorticoid metabolism dysregulation remain unclear, however, there is evidence that it may be related to inflammation. In vitro studies have demonstrated that pro-inflammatory markers upregulate 11βHSD1 expression in adipocytes, potentially explaining increased expression of this enzyme in obesity. Previous work has also demonstrated that the glucocorticoid metabolites produced by 5αR1 lack the metabolic effects of the parent glucocorticoid, but retain its anti-inflammatory properties, indicating that increased expression of hepatic 5αR1 may serve to dampen down inflammation in the liver. The hypotheses addressed in this thesis are that in obesity, inflammation regulates adipose glucocorticoid metabolism through 11βHSD1, and that hepatic glucocorticoid metabolism regulates the inflammatory state of the liver through 5αR1. The role of inflammation in the regulation of 11βHSD1 was assessed in vivo in mice treated with the anti-inflammatory compound sodium salicylate (salicylate). In diet-induced obese mice, salicylate downregulated 11βHSD1 expression and activity selectively in visceral adipose tissue, alongside improved glucose tolerance, reduced plasma non-esterified fatty acids, and changes in adipose lipid metabolism. 11βHSD1-deficient mice fed a high-fat diet were resistant to the insulin sensitising effects of salicylate treatment. These results indicate a novel role for 11βHSD1 down-regulation in mediating the insulin sensitising effect of anti-inflammatory treatment. The mechanisms underpinning the anti-inflammatory properties of 5α-reduced glucocorticoids were explored in vitro and in vivo. In lipopolysaccharide-stimulated murine macrophages, both 5α-reduced glucocorticoid metabolites tested, namely 5α-dihydrocorticosterone (5αDHB) and 5α-tetrahydrocorticosterone (5αTHB), suppressed tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) release, although to a lesser extent than corticosterone (B). Similar to B, both 5αDHB and 5α THB suppressed phosphorylation of intra-cellular inflammatory signalling mitogen-activated protein kinases (MAPK) proteins c-Jun N-terminal kinase (JNK) and p38, as well as increasing protein expression of MAPK phosphatase-1 (MKP-1). Treatment of phorbol ester-stimulated HEK293 kidney cells with these 5α-metabolites revealed that 5αDHB suppressed nuclear factor κB (NFκB) and activator protein-1 (AP-1) activation to a similar extent to that of B, whilst 5αTHB increased activation of these pro-inflammatory transcription factors, indicating cell-specific effects of 5αTHB. In conclusion, reduced intra-adipose glucocorticoid regeneration by 11βHSD1 mediates the insulin sensitising effects of salicylate, suggesting that altered glucocorticoid metabolism may reflect altered intra-adipose inflammation in obesity. Furthermore, these data support the concept that this enzyme provides a therapeutic target in obesity-related metabolic disorders. 5α-reduced metabolites of glucocorticoids have similar anti-inflammatory properties to the parent glucocorticoid, indicating that the elevated hepatic levels of 5α-reductase in obesity may be a protective mechanism to limit the adverse metabolic effects of glucocorticoids upon the liver, but maintain the beneficial anti-inflammatory properties. These 5α-reduced glucocorticoid metabolites may provide a potential therapeutic treatment as selective glucocorticoid receptor modulators for inflammatory conditions.
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Stark, Jennifer L. "Social Stress and the induction of Glucocorticoid resistance in male mice /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486401895208126.
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Trebble, Peter. "Glucocorticoid receptor function : new insights from genetic and chemical biology approaches." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/glucocorticoid-receptor-function-new-insights-from-genetic-and-chemical-biology-approaches(b55c612b-eda1-4908-a0df-ec916f03ade2).html.
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Glucocorticoids (Gc) are vital for development, maintenance of glucose homeostasis and the resolution of inflammation. As potent modulators of the immune response Gc are routinely prescribed in the management of a variety of inflammatory diseases including asthma and rheumatoid arthritis. However clinical use of Gc is limited by variation in patient sensitivity to Gc treatment and development of a wide range of side effects. In this thesis I present two studies that have advanced our understanding of Gc action in vivo. The first defines and characterises the cause of familial glucocorticoid resistance, and the second describes the action of two potent non-steroidal Gc in a cell line model. Familial Gc Resistance: Cases of primary generalised Gc resistance are very rare and typically present as mineralocorticoid and androgen excess leading to hypertension, hypokalemia and hirsutism. Gc resistance is attributed to loss of function mutations within the glucocorticoid receptor (GR). Here I identify a family with a novel mutation in GR exon 6 that gives rise to a very mild phenotype. Analysis of transformed patient peripheral blood lymphocytes revealed a 50% reduction in full length GR but no expression of a mutant form. As this did not rule out expression in vivo, the mutant receptor (Δ612GR) was characterised in a cell line. Investigation using reporter genes revealed that Δ612GR lacked any activity, but had dominant negative action when co expressed with full length GR. In response to Gc Δ612GR was not phosphorylated or targeted for degradation. Fluorophore tagged Δ612GR was unable to translocate to the nucleus in response to Gc, but delayed the translocation of full length GR when co-expressed. Together this indicates that Δ612GR is unable to bind ligand but has dominant negative action upon full length GR most likely due to heterodimerisation. Therefore I describe a novel GR mutation that results in Gc resistance but presents with a mild very phenotype. Novel Non-steroidal Gc: Non-steroidal Gc can be used as tools to determine how ligand structure directs GR function. Here I describe two highly potent non steroidal Gc ligands, GSK47867A and GSK47869A which alter the kinetics of receptor activity. Treatment with either ligand induces slow GR nuclear translocation, promotes GR nuclear retention and prolongs transcriptional activity following ligand withdrawal. Crystal structure analysis revealed that GSK47867A and GSK47869A specifically alter the surface charge of the GR at a site important for Hsp90 binding. GR bound to GSK47867A and GSK47869A shows prolonged activity in the presence of Hsp90 inhibitor geldanamycin. Therefore this work identifies a new chemical series that could prolong GR activity due to altered pharmacodynamics rather than altered pharmacokinetics.In summary this work uses a combination of genetic and chemical biology approaches to broaden our understanding of GR function. Characterisation of naturally occurring GR mutations gives insight into the complex function of the GR, and non-steroidal Gc act as useful tools that will aid in the design of improved therapeutics.
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Lynch, James Thomas. "Molecular mechanisms conferring resistance/sensitivity to glucocorticoid-induced apoptosis during cytotoxic stress." Thesis, University of Manchester, 2009. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:151882.
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During stress conditions, glucocorticoids are secreted and exert most of their physiological responses by binding to and modulating the transcriptional activity of the glucocorticoid receptor (GR). Once activated, GR can regulate numerous cellular processes including inflammation, development, growth, metabolism and apoptosis. Although glucocorticoids have been used in the treatment of leukaemia for over 50 years, with the molecular mechanisms by which steroids exert their pro-apoptotic effect, the pathways responsible for the development of resistance to glucocorticoid treatment, as well as their role in the programmed cell death in other tissue types have not been precisely defined. Research has demonstrated that glucocorticoid-induced apoptosis requires a transcriptionally active form of GR and is executed by the induction of the intrinsic pathway of apoptosis. In addition, GR is regulated by diverse types of cytotoxic stress; including UV irradiation and hypoxia, which alter the receptor’s transcriptional activity through multiple mechanisms. These include post-translational modifications, subcellular localisation and interaction of the receptor with co-regulator proteins. The aims of this study are to identify novel members of the Bcl-2 family that are regulated at the transcriptional level by GR in both leukaemia and other tissue types where glucocorticoids promote cell survival. In addition, the molecular crosstalk between signalling pathways activated by cytotoxic stress conditions and the mechanisms by which they differentially modulate the apoptotic response will be investigated. Results obtained in this study have identified putative glucocorticoid response elements in the promoters of the BH3-only pro-apoptotic gene NOXA and the anti-apoptotic gene Mcl-1 and confirmed that both NOXA and Mcl-1 are direct GR transcriptional targets. The glucocorticoid-mediated expression of NOXA and Mcl-1 alters their protein-protein interaction pattern, leading to the subsequent destabilisation of Mcl-1 in cell lines that undergo glucocorticoid-induced apoptosis. Investigation into the effects that other cytotoxic stress pathways have on GR function have revealed that serine 226 phosphorylation of GR by JNK occurs in a rapid and transient manner. Phosphorylation has inhibitory effects on the transcription of GR targets in a gene-specific manner, including the differential regulation of NOXA gene expression. During hypoxia, glucocorticoids differentially regulate the GR and HIF-1 target genes, NOXA and Mcl-1, altering the apoptotic response. This study has provided additional insight into the molecular mechanisms that govern glucocorticoid-induced programmed cell death and revealed mechanisms by which glucocorticoids and cytotoxic stress pathways crosstalk, regulating apoptosis.
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Dhanda, Ashwin Deep. "Mechanisms of glucocorticoid resistance in inflammatory diseases of the gut and liver." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665487.
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Glucocorticoids (GCs) are widely used to treat inflammatory diseases of the gut and liver. However, they are ineffective in up to a third of patients. In ulcerative colitis (UC) such GC resistant individuals require a colectomy, while patients with severe alcoholic hepatitis (AH) develop fatal progressive liver failure. Early stratification of these high-risk patients is critical to improve our understanding of the mechanisms of GC resistance and also for the development of better therapies. The work presented in this thesis aimed to extend the application of a candidate biomarker of GC resistant disease from UC to AH. Based on this, differential lymphocyte responses to GCs were then interrogated, and the effect of interleukin-2 on GC responsiveness assessed. An evaluation of the role of different T helper (Th) cell subsets in driving the GC resistant phenotype was then conducted, followed by an investigation of the role of monocytes in shaping these T cell responses to GCs. These studies have confirmed that the in vitro effect of GCs on lymphocyte proliferation corresponds with clinical outcome in AH as well as UC, highlighting the role of T cell responses. Blockade of IL-2 improved GC sensitivity in vitro and investigation of intracellular signalling pathways demonstrated that there was impaired GC regulation of the pro-inflammatory transcription factor NFKB in GC resistant cells. NFKB can induce Th17 cell differentiation and IL-17 expression was found to be refractory to GC suppression in CD4+ T cells. Toll-like receptors (TLRs) were then shown to influence monocyte-mediated CD4+ T cell differentiation in both man (in vitro) and mouse (in vivo). Monocyte subsets were critical in determining this T cell fate, and innate immune responses are therefore a key potential driver of the GC resistant phenotype. This work has led to the development of a protocol for a Phase II clinical trial of IL-2 blockade in GC resistant AH and also further mechanistic studies to evaluate the role of monocytes in GC resistant diseases.
15
Strand, Victoria. "Effects of nitrogen dioxide on airway responsiveness in allergic asthma /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980821stra.
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Nicholson, Lindsay. "The role of NFκB in glucocorticoid resistance in childhood acute lymphoblastic leukaemia (ALL)." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493230.
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Glucocorticoids (GC) are pivotal agents used in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Although mutation or loss of the glucocorticoid receptor (GR) leads to GCresistance in vitro, genetic aberration of the GR is rare in clinical samples. Expression-array studies have shown that commonly-upregulated genes associatec with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and kBa, which negatively interact with components of the pro-survival NFkB pathway and may be critical determinants of GC-sensitivity.
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Huang, Edmond Y. Mathews Suresh T. "A novel role for fetuin-A in the pathophysiology of glucocorticoid-mediated insulin resistance." Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/SPRING/Nutrition_and_Food_Science/Thesis/Huang_Edmond_42.pdf.
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Chachi, Latifa. "New insight into the molecular mechanisms of corticosteroid resistance in asthma." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/29242.
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Although corticosteroids are very efficient in managing asthma and other inflammatory diseases, a small percentage of patients affected by “severe asthma” fail to respond even to high doses of oral glucocorticoids. It is therefore important to try to understand the potential mechanisms behind this insensitivity to corticosteroid therapy in order to be able to effectively control asthma in this patient subset. We have decided to focus on one particular channel called K[subscript Ca]3.1, a calcium-activated potassium channel. First, emerging evidence in the literature to date has strongly supported a significant role for K[subscript Ca]3.1 channel in the pathophysiology of asthma. K[subscript Ca]3.1 channel is expressed by several inflammatory and structural airway cells including mast cells and human bronchial smooth muscle (HBSM). Therefore these channels might serve as new targets for the treatment of lung diseases. Here we established a cellular model of corticosteroid insensitivity consisting of primary HBSM cells exposed to two cytokines TNF-α and IFN-γ. Under these conditions, HBSMC exhibit a marked production of different pro-asthmatic chemokines like CCL5, CX3CL1, CCL11 and CXCL10 that are completely resistant to corticosteroid treatment. In this model, we found that although K[subscript Ca]3.1 channel expression did not change between healthy control, asthmatic and COPD subjects, K[subscript Ca]3.1 channel blockers (ICA-17043 and TRAM-34) were able to inhibit the production of corticosteroid-resistant chemokines either directly via the suppression of gene expression or indirectly via the restoration of the anti-inflammatory action of fluticasone. We also found that K[subscript Ca]3.1 channel blockers restored cell sensitivity to corticosteroid in cytokine-treated HBSMC by re-establishing the transactivation function of fluticasone via the prevention of dephosphorylation of Glucocorticoid Receptors (GRα) at Ser[superscript 211] and induction of anti-inflammatory genes such as Glucocorticoid-induced leucine zipper (GILZ). The likely mechanism of this restoration of corticosteroid sensitivity by K[subscript Ca]3.1 channel blockers is via the inhibition of protein phosphatase 5 (PP5) expression found to be up-regulated in steroid resistant conditions.
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Schoenle, Laura Ann. "Coping with Chronic Infection: The Role of Glucocorticoid Hormones in Mediating Resistance and Tolerance to Parasites." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/86535.
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Parasitic infections are ubiquitous, but the consequences to hosts can vary substantially. Variation in the consequences of infection can be related to individual differences in the use of two parasite defense strategies, resistance and tolerance. Resistance entails reducing parasite burden by removing parasites or restricting parasite reproduction. Tolerance involves minimizing the costs associated with a given parasite burden. Genetic variation, environmental conditions, and life history stage can contribute to variation in resistance and tolerance, but the physiological mechanisms that underlie investment in each strategy are not well understood. I proposed that glucocorticoid hormones, which mediate responses to challenges in the physical and social environment in vertebrates, might alter host investment in resistance and tolerance (Chapter I). Glucocorticoids influence a suite of physiological processes including immune function, resource allocation, and tissue growth, all which could alter resistance and tolerance. Using a combination of observational and experimental studies, I test the hypothesis that glucocorticoids mediate resistance and tolerance to infection in red-winged blackbirds (Agelaius phoeniceus) infected with Haemosporidians, including malaria (Plasmodium) and malaria-like (Haemoproteus and Leucocytozoon) parasites. I performed a medication experiment (Chapter II) to identify the physiological consequences of Haemosporidian infection and explored the relationships between glucocorticoids and parasite resistance and tolerance in both an observational field study and a hormone manipulation experiment (Chapters III and IV). Medication treatment effectively reduced Plasmodium burden, increased hematocrit and hemoglobin, and reduced the rate of red blood cell production (Chapter II). In an observational field study (Chapter III), red-winged blackbirds with higher plasma glucocorticoid concentrations maintained higher hematocrit than expected for their parasite burdens, suggesting a positive association between glucocorticoids and tolerance. In this study, I found no support for a relationship between glucocorticoids and resistance. However, experimental elevation of glucocorticoids (Chapter IV) yielded nearly opposite results: the higher of two doses of glucocorticoids increased Plasmodium burdens and caused a decrease in body mass with increasing parasite burden, indicative of a decrease in tolerance. I discuss possible causes of the differences in our observational and experimental studies and the implications of my work for future studies of individual variation in parasite tolerance (Chapter V).Ph. D.
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Riebold, Mathias. "Investigations on the role of Hsp90 in the pathogenic glucocorticoid resistance of corticotroph pituitary adenomas." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-177888.
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The main function of glucocorticoids in corticotroph cells is to suppress proopiomelanocortin, the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing’s disease is a rare but severe neuroendocrine condition caused by partially glucocorticoid resistant corticotroph adenomas, which consequently secrete excessive amounts of ACTH in an uncontrolled fashion. The patients suffer from chronic hypercortisolism due to excessive stimulation of the adrenal glands by ACTH to produce glucocorticoids. Impairing mutations of the glucocorticoid receptor (GR) only sporadically explain the reduced glucocorticoid sensitivity in the adenomas – the molecular mechanism behind the partial resistance is poorly understood.
The function of GR depends on direct interactions with the molecular chaperone Hsp90. Both the reduction and overexpression of Hsp90 impedes GR activity in different experimental settings. Therefore, the expression of the inducible Hsp90α isoform was determined in biopsy specimens of corticotroph pituitary adenomas from patients with Cushing’s disease. Its strong overexpression compared to normal human pituitary cells paved the way to study its role in the function of corticotroph adenomas using small molecules which target Hsp90.
The three distinct Hsp90 inhibitors 17–AAG, Novobiocin and Silibinin showed antiproliferative effects in AtT–20 cells through the degradation of the oncogenic client kinase Cdc2, a hallmark of pharmacologic inhibition of Hsp90. Surprisingly, only the N–terminal Hsp90 inhibitor 17–AAG caused the degradation of GR, as was reported also for other Geldanamycin–based Hsp90 inhibitors. Neither Silibinin nor the C–terminal Hsp90 inhibitor Novobiocin affected GR protein levels. These converging effects led to the assumption that both compounds bind to the same domain in Hsp90. It was shown here that Novobiocin displaces Silibinin from the C–terminal domain of Hsp90, and that these compounds dissociate mature GR from Hsp90 at the biochemical level. As a result, increased levels of mature receptor were present in the cell able to bind glucocorticoids with high affinity. This novel molecular mechanism proved to potentiate GR transcriptional activity in AtT–20 cells. The potentiation in GR activity also led to enhanced suppression of ACTH elicited by low concentrations of Dexamethasone in AtT–20 cells and in primary cultures of human corticotroph adenomas from patients with Cushing’s disease. In contrast, Silibinin did not show effects on rat normal pituitary cells. Finally, Silibinin reduced tumor growth, partially reverted hormonal alterations, and alleviated symptoms in a mouse allograft model for Cushing’s disease.
These results suggest that the regulation of GR sensitivity by overexpressed Hsp90 may represent a pharmacologically reversible mechanism in the pathogenesis of this disease. Together, a proof of principle is provided that the clinically safe Hsp90 inhibitor Silibinin potentially restores glucocorticoid sensitivity in corticotroph adenomas in vitro and in vivo, and that it might be used to treat Cushing’s patients in the future.
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How, Stephen Christopher. "Effect of acute and chronic pressure-threshold inspiratory muscle training on upper and lower airway function." Thesis, Brunel University, 2010. http://bura.brunel.ac.uk/handle/2438/5517.
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There is evidence to suggest that inspiratory muscle training (IMT) may influence the functional properties of the muscles of the upper (UA) and lower (LA) airway. However, the nature and functional relevance of this influence is currently unclear. This thesis examined the effect of acute and chronic IMT in the context of UA and LA function. The ability of IMT to activate the UA dilator muscles, genioglossus (GG) and geniohyoid (GH), was examined using magnetic resonance imaging (MRI), as was the effect of chronic training on these muscles. In addition, the effect of acute and chronic IMT upon LA resistance (Rrs) and function was investigated in people with asthma using the Forced Oscillation Technique and conventional spirometry. For the UA, an acute bout of IMT at 60% maximal inspiratory mouth pressure (MIP) resulted in significant GG and GH activation (P < 0.001) as demonstrated by increases in the transverse relaxation time of muscle water (T2). Despite this, MRI was unable to detect any effect of chronic IMT upon UA function. For the LA, the usual increase in Rrs, following deep inhalation (DI) in people with asthma was attenuated with both single and multiple breaths against a pressure-threshold load equal to 50% MIP. However, six weeks IMT had no effect on baseline airway function or response to DI. In conclusion, an acute effect of pressure-threshold IMT upon UA and LA function was demonstrated. A strong rationale for a beneficial influence of chronic pressure-threshold IMT was therefore demonstrated. However, the data were insufficient to either reject, or accept the hypothesis that IMT exerts more than a transient influence upon UA and LA function, but insights are presented that support the need for further investigations.
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McBeth, Lucien Reiter. "Glucocorticoid Receptor beta Increases the Migration of Human Urothelial Carcinoma Cells." University of Toledo Health Science Campus / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1467031531.
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Livingston, Eric. "Effect of environmental factors (smoking and allergen exposure) on corticosteroid resistance in asthma." Thesis, University of Glasgow, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433613.
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Lowe, Alexander Paul. "The role of viral and bacterial infections in asthma exacerbations and corticosteroid resistance." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/47342/.
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Asthma is a chronic inflammatory disease of the airways characterised by early and late asthmatic responses (EAR & LAR) to allergen, airways hyperresponsiveness (AHR) to inhaled spasmogens, airway inflammation and airway oedema. Viral infections and lipopolysaccharide (LPS) from bacteria and environmental sources contribute to exacerbations of asthma and the development of insensitivity to corticosteroids. Complete insensitivity to oral corticosteroids is rare and most patients lie on a continuum of steroid responsiveness. This thesis aimed to examine the effect of viral infection and LPS in a guinea-pig model of asthma and determine the sensitivity to inhaled and systemic corticosteroids. Sensitised guinea-pigs challenged with ovalbumin displayed EAR, LAR, AHR to histamine, airways inflammation and airway oedema. Inoculation of guinea-pigs with parainfluenza-3 virus alone induced AHR to histamine and airway inflammation. However this response was not consistent. Inhaled LPS alone induced an immediate bronchoconstriction, AHR, airway inflammation and oedema and goblet cell hyperplasia. LPS co-administered with ovalbumin exacerbated the allergen response by lengthening the EAR, prolonging the bronchoconstrictor response to histamine, increasing airway inflammation and oedema and goblet cell hyperplasia. In guinea-pigs challenged with ovalbumin alone, treatment with inhaled fluticasone propionate (FP) and inhaled and systemic dexamethasone decreased the LAR, abolished AHR, airway inflammation and oedema. Responses to LPS alone were not reduced by inhaled dexamethasone or FP but partially reduced by systemic dexamethasone. Ovalbumin and LPS combined responses were insensitive to inhaled corticosteroids, except lavage fluid protein. These responses were partially sensitive to systemic dexamethasone, with the prolonged EAR, inflammation and airway oedema all reduced. The data in this thesis suggests that LPS inhalation exacerbates ovalbumin-induced functional and inflammatory responses rendering them insensitive to inhaled corticosteroids but partially sensitive to systemic corticosteroids. Thus, the experimental combination of ovalbumin with LPS might represent a useful preclinical model of corticosteroid-insensitive airway inflammation.
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Flood, Lars. "Glucocorticosteroid therapy and steroid resistance in inflammatory bowel disease /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-020-6/.
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Riebold, Mathias [Verfasser], and Mathias [Akademischer Betreuer] Schmidt. "Investigations on the role of Hsp90 in the pathogenic glucocorticoid resistance of corticotroph pituitary adenomas / Mathias Riebold. Betreuer: Mathias Schmidt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/106561070X/34.
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Marchica, Cinzia Loreta 1984. "Allergen-induced asthma is decreased in decorin-deficient mice." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116096.
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Decorin, is an extracellular matrix proteoglycan with important biological functions. Decorin deficiency affects collagen fibrillogenesis, airway mechanics, airway-parenchymal interdependence, and airway smooth muscle proliferation and apoptosis. We questioned whether decorin deficiency would alter allergen-induced asthma in a mouse model. Decorin-/- and decorin+/+ mice (C57Bl/6) were sensitized and challenged with ovalbumin. Control animals received saline. Responsiveness was assessed at baseline and after delivery of increasing concentrations of methacholine. Histological analyses were also performed. Decorin deficiency resulted in more modest hyperresponsiveness. Respiratory resistance and elastance along with tissue damping and tissue elastance, were increased in ovalbumin decorin +/+ and decorin-/-, but more so in decorin+/+ . Airway resistance was increased in ovalbumin decorin+/+ only. Inflammation and collagen staining within the airway wall, were increased in ovalbumin decorin+/+ mice only; whereas biglycan was significantly increased in ovalbumin decorin-/- mice only. These results reflect the role of decorin in the development of allergen-induced asthma.
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Gallagher, Kayleigh M. "Identification of ESRRB and SOX2 as novel mediators of the glucocorticoid response in acute lymphoblastic leukemia." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1093.
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Resistance to glucocorticoid (GC) therapy results in poor prognosis for acute lymphoblastic leukemia (ALL) patients. Utilizing a whole genome shRNA screen our lab identified several novel mechanisms of GC resistance. My thesis work established that an orphan nuclear receptor, the Estrogen Related Receptor Beta (ESRRB), is critical for induction of apoptotic genes following treatment with the GC dexamethasone. ESRRB has mostly been implicated in maintenance of pluripotency in mouse embryonic stem cells. We find that repression of ESRRB results in GC resistance in ALL and define ESRRB as a novel cooperating transcription factor in GC-induced gene expression. We also show that agonists to ESRRB synergize with dexamethasone and increase dexamethasone induced apoptosis in relapse ALL patient samples.
Interestingly, our shRNA screen identified another factor important in stem cell maintenance: SOX2. While we originally hypothesized that ESRRB and SOX2 may cooperate in ALL, RNA-sequencing studies revealed that these factors mediate GC resistance by independent mechanisms. Our data define SOX2 as a repressor of key signaling pathways in ALL. Upon SOX2 knockdown, we observe activation of pro-survival gene expression including activation of the MAPK pathway, which has previously been implicated in GC resistance. MAPK activation may be explained by an increase in EGFR expression observed in Sox2 knockdown cells and GC resistant patients, suggesting EGFR inhibitors may re-sensitize patients to GCs. Overall my thesis work identifies mechanisms of GC resistance in ALL and utilizes these findings to define novel therapeutic strategies for GC resistant ALL patients.
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Goodrich, Geoffrey G. "Detoxification gene polymorphisms, patient demographics, environmental exposures and potential relationships with childhood asthma cross-sectional case study /." abstract and full text PDF (free order & download UNR users only), 2008. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3326205.
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Barck, Charlotte. "Airway responses to NO₂ and allergen in asthmatics /." Stockholm : Karolinska University Press, 2005. http://diss.kib.ki.se/2005/91-7140-273-X/.
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Lê, Tuan Thành. "Lung function by plethysmography : a new method in Vietnam for asthma diagnosis." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0341/document.
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La fréquence de l’asthme augmente au Vietnam, mais les moyens de diagnostic et d’évaluation fonctionnelle sont limités. Une étude précédente utilisant la technique des oscillations forcées a montré une différence de résistance des voies aériennes entre enfants français et vietnamiens à l’âge de 10 ans mais pas à 6 ans. Si l’hypothèse d’une différence ethnique significative est correcte, alors des différences semblables devraient aussi exister à l’âge adulte. Pour tester l’hypothèse, une étude par pléthysmographie a été mise en place pour mesurer la résistance des voies aériennes et la résistance spécifique des voies aériennes chez de jeunes adultes sains en France et au Vietnam. Nous avons profité de l’étude pour établir des valeurs de référence pour les volumes pulmonaires dans ces populations. La résistance des voies aériennes est significativement plus grande chez les sujets vietnamiens que chez les caucasiens, mais il n’y a aucune différence de résistance spécifique des voies aériennes. Au final, l’étude ne montre pas de différence de calibre des voies aériennes normalisé pour le volume pulmonaire liée l’ethnie, à l’âge adulte. La taille debout est le facteur prédictif le plus important pour la capacité pulmonaire totale, tandis que l’ethnicité est un facteur important pour la capacité vitale et le rapport du volume résiduel à la capacité pulmonaire totale. Cette étude est la première qui fournit des valeurs de référence pour la résistance des voies aériennes, la résistance spécifique des voies aériennes et les volumes pulmonaires par pléthysmographie chez l’adulte vietnamien. La pléthysmographie a été validée à Hanoi et l’étude a permis la formation d’un nouveau groupe de travail sur le diagnostic et la prise en charge de l’asthme au VietnamDespite the increasing prevalence of asthma in Viet Nam, the country has limited means for respiratory function testing. A previous study using the forced oscillation technique suggested lower respiratory resistance between French and Vietnamese children at 10 years but not 6 years of age. If the hypothesis of a significant ethnic difference in airway caliber is correct, then similar differences should exist at adult age. To test the hypothesis, a plethysmographic study was set up to measure airway resistance and specific airway resistance in healthy young adults in France and Viet Nam. We took advantage of the study to provide reference values for lung volume in these populations. Airway resistance is significantly larger in Vietnamese than in Caucasians but there is no difference in specific airway resistance. Altogether the study does not support the consequence of a putative ethnic difference in childhood airway caliber on airway resistance normalized for lung volume at adult age. The standing height is the best predictor of the total lung capacity, while ethnicity is an important predictor of vital capacity and of the residual volume to total lung capacity ratio. This is the first study which provides reference values for airway resistance, specific airway resistance and lung volumes by plethysmography in healthy young Vietnamese adults. Plethysmography was validated in the north of Viet Nam, and the study allowed initiating a young working group on asthma diagnosis in Vietnam
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Calixto, Marina Ciarallo 1980. "Efeito da ativação da AMPK na exacerbação da inflamação pulmonar alérgica em camundongos obesos." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308911.
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Orientador: Edson AntunesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A obesidade e a asma são doenças prevalentes e crescentes, e ambas têm impacto significativo na saúde pública mundial. O aumento simultâneo da prevalência da asma e da obesidade tem levado investigadores a sugerir que a obesidade possa ser um fator importante no desenvolvimento da asma, ou até piorar um quadro de asma pré-existente. Numerosos estudos populacionais conduzidos em todo o mundo indicam que a prevalência de asma é maior em indivíduos obesos versus magros. Além disso, diversos estudos prospectivos, tanto em adultos quanto em crianças, indicam que o risco relativo da incidência de asma aumenta com o índice de massa corporal (IMC). A obesidade também piora o controle medicamentoso da asma e a gravidade desta doença. Recentemente, diversos dados emergiram indicando que a inflamação associada à obesidade pode aumentar a propensão para o desenvolvimento de asma. Acredita-se que a resistência à insulina associada à obesidade desempenha importante papel no desenvolvimento da asma, explicando, ao menos em parte, a associação da asma com obesidade. Relatos recentes indicam uma alta prevalência de resistência à insulina em pacientes obesos e asmáticos versus obesos não asmáticos, sugerindo que a resistência à insulina possa contribuir com este fenótipo. Baseado nestas informações, o objetivo deste trabalho foi verificar se doenças metabólicas associadas à obesidade, tal como a resistência à insulina, podem estar envolvidas na exacerbação da asma associada à obesidade. No presente estudo observamos que o tratamento de camundongos obesos com metformina corrige a resistência à ação sistêmica da insulina. Além disso, metformina normaliza o trânsito dos eosinófilos da medula óssea até o lúmen em animais obesos e desafiados com OVA. Essa normalização parece ser mediada pela ativação da AMPK no pulmão e diminuição das concentrações de TNF-? e NOx no LBA e inibição da expressão de iNOS induzida pelo fator de transcrição NF-?B no pulmão. Além disso, ao normalizar o tráfego de eosinófilos da região peribronquiolar para a luz das vias aéreas, o tratamento com metformina induz concomitante diminuição do acúmulo de eosinófilos na medula óssea devido à regulação positiva da expressão de moléculas de adesão VLA-4 e Mac-1 na superfície das células e posterior aumento da resposta adesiva à ICAM-1 e VCAM-1. Os resultados descritos neste estudo parecem confirmar a hipótese que a resistência à insulina, resultante da obesidade, medeia a exacerbação da resposta inflamatória pulmonar observada em animais obesos. Dessa forma, ao corrigir a resistência à insulina sistêmica através da ativação da AMPK, camundongos sensibilizados obesos aceleram o início do processo de resolução da inflamação pulmonar alérgica
Abstract: Obesity and asthma are prevalent and increasing diseases, and both have significant impact on global public health. The increase in prevalence of asthma and obesity has led researchers to suggest that obesity may be an important factor in the development of asthma, or even worse the pre-existing asthma. Numerous populational studies conducted around the world indicate that the prevalence of asthma is higher in obese versus lean person. In addition, several prospective studies, both in adults and in children, indicate that the relative risk of incident asthma increases with body mass index (BMI). Obesity also worsens the drug therapy of asthma and the severity of this disease. Recently, several data emerged showing that the inflammation associated with obesity increase the propensity for development of asthma. It is believed that insulin resistance associated with obesity plays an important role in the development of asthma, explaining, at least in part, asthma associated with obesity. Recent reports indicate a high prevalence of insulin resistance in obese asthmatics versus obese non-asthmatics patients, suggesting that insulin resistance may contribute to this phenotype. Based on this information, the purpose of this study was to determine whether metabolic diseases associated with obesity such as insulin resistance, are involved in asthma exacerbation associated with obesity. In the present study we observed that obese mice treated with metformin, impairs the resistantance to the systemic action of insulin. Furthermore, in obese mice challend with OVA, metformin normalizes the transit of eosinophils from bone marrow to the lung lumen. This normalization is mediated by AMPK activation in the lung, as well as decreased concentrations of TNF-? and nitrite and nitrate in BAL fluid accompanied by the inhibition of NF-?B induced iNOS expression in the lung. Furthermore, by normalizing the eosinophils trafficking from peribronchiolar region to airway lumen, metformin treatment induces concomitant reduction in the accumulation of eosinophils in bone marrow through the upregulation of adhesion molecules VLA-4 and Mac-1 on cell surface and subsequent increase in the adhesive response to plates coated with ICAM-1 and VCAM-1. Our data seem to confirm the hypothesis that insulin resistance resulting from obesity mediates the exacerbation of airway inflammation in high fat-diet mice. Thus, by normalizing the systemic insulin resistance through the atictivation of AMPK, obese sensitized mice progress to resolution of allergic airway inflammation
Doutorado
Farmacologia
Doutora em Farmacologia
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Dalle, Heloïse. "Rôle du récepteur adipocytaire des glucocorticoïdes dans les troubles métaboliques liés à un traitement par la corticostérone Adipocyte glucocorticoid receptor deficiency promotes adipose tissue expandability and improves the metabolic profile under corticosterone exposure Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration." Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS065.pdf.
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Les glucocorticoïdes (GC) font partie des médicaments les plus prescrits en raison de leurs propriétés anti-inflammatoires et immunosuppressives, cependant à fortes doses ils sont responsables du développement d’un diabète cortico-induit et d’une lipodystrophie. La contribution du récepteur adipocytaire des glucocorticoïdes (GR) dans ces effets délétères reste à ce jour peu documentée. L’objectif de ce travail de thèse était de déterminer dans un contexte d’hypercorticisme le rôle précis du GR adipocytaire dans le développement de l’insulino-résistance et des troubles métaboliques associés. Pour mener à bien ce projet, le laboratoire a généré un modèle murin d’invalidation conditionnelle du GR spécifiquement dans l’adipocyte (AdipoGR-KO), soumis à un traitement par la corticostérone. Le phénotypage métabolique montre chez les animaux AdipoGR-KO une augmentation de l’adiposité associée, paradoxalement, à une amélioration de la tolérance au glucose, de la sensibilité à l’insuline, du profil lipidique et de la stéatose hépatique. Le stockage préférentiel et bénéfique des lipides dans les dépôts adipeux nous a incité à étudier les mécanismes mis en jeu lors du développement physiopathologique du tissu adipeux, et en particulier de sa vascularisation. De façon étonnante, nos résultats indiquent un fort développement du réseau vasculaire des dépôts adipeux associé à une induction de l’expression du facteur pro-angiogénique VEGF-A et de son régulateur transcriptionnel HIF-1α. Ainsi, nous montrons pour la première fois que le GR pourrait être un facteur limitant de l’expansion du tissu adipeux via l’inhibition du processus d’angiogenèseGlucocorticoids (GC) are among the medications most commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses can lead to side effects including GC-induced diabetes and lipodystrophy. The contribution of adipocyte glucocorticoid receptor (GR) in the molecular mechanisms of these complications remains to be investigated. The goal of this study was to determine the precise role of the GR in the development of insulin-resistance and associated metabolic dysregulations in a context of hypercorticism. For this purpose, we have generated an inducible mouse model of GR invalidation specifically in the adipocyte (AdipoGR-KO), which was submitted to a four-week corticosterone treatment. Metabolic phenotype of AdipoGR-KO mice showed an increase of fat mass associated with a paradoxical improvement of glucose tolerance, insulin sensitivity, lipid profile and liver steatosis compared to WT mice. Preferential and beneficial fat storage in adipose tissue prompted us to investigate the mechanisms involved in the excessive development of adipose tissue, in particular the vascularization. Surprisingly, our results showed a higher development of capillary network in fat pads of AdipoGR-KO mice, associated with a strong induction of the angiogenic factor VEGF-A and its transcriptional regulator HIF-1α. Thus, we show for the first time that GR could be a limiting factor of adipose tissue expansion through the inhibition of the angiogenic process
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Sribanditmongkol, Vorachai. "Effects of Psychological Stress on Glucocorticoid Sensitivity of Inflammatory Response to Influenza Vaccine Challenge in Healthy Military College Students." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366195257.
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Karaki, Soumaya. "Effets immunorégulateurs de la protéine GILZ (Glucocorticoid-induced leucine Zipper) sur la fonction des cellules dendritiques dans la réponse immunitaire allergique : étude Clinique et expérimentale." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00923138.
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Une cellule dendritique (CD) qui exprime le facteur de transcription GILZ durant l'apprêtement de l'antigène et sa présentation aux cellules effectrices, génère des lymphocytes T régulateurs (LTregs) CD25high Foxp3+ sécréteurs d'IL-10. La production de GILZ est dépendante de l'action des glucocorticoïdes, de l'IL-10 et du TGF-.Nous avons mis en évidence chez l'homme qu'une corticothérapie orale de 48h induit l'expression de GILZ dans les cellules présentatrices de l'antigène circulantes (CPAs) de sujets allergiques. Les CPAs isolées après la corticothérapie génèrent des LTregs CD25high Foxp3+ IL-10+ spécifiques de l'allergène.Nous également constaté in vitro que les mastocytes participent à l'activation des CDs au cours des réactions allergiques en régulant l'expression de GILZ. Les médiateurs d'origine mastocytaire, dont l'histamine, diminuent l'expression de GILZ dans les CDs et altèrent ainsi leur capacité à activer des LTregs. Nous avons identifié le mécanisme par lequel l'histamine diminue l'expression de GILZ dans les CDs humaines. L'histamine inhibe l'activité transcriptionnelle de Foxo3, un facteur de transcription régulant l'expression de GILZ. Enfin, nous avons démontré que des souris transgéniques qui surexpriment GILZ constitutivement dans les CDs sont protégées contre le développement de l'asthme allergique. L'ensemble de ces résultats permet d'envisager de nouvelles stratégies d'immunomodulation dans l'allergie, centrée sur la régulation de l'expression de GILZ dans les CDs.
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Simões, Joana de Sousa Azevedo. "Contribution to the discriminant power of some of the variables involved in the staging of severe equine asthma syndrome." Doctoral thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2020. http://hdl.handle.net/10400.5/19939.
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Tese de Doutoramento em Ciências Veterinárias na especialidade de ClínicaSevere Equine Asthma Syndrome (EAS) is a highly prevalent, chronic and recurrent respiratory disease which appears to be related to equine domestication. Due to its insidious nature, treatment may sometimes be frustrating and severe economic loses occur. Genetically susceptible individuals develop airway inflammation, hyperresponsiveness and obstruction when exposed to environments with high concentrations of respirable dust particles, which include mould spores, mites, endotoxins, pollen and other antigenic materials. These hazardous respirable dust concentrations are usually found in traditional equine housing systems, while lower concentrations tend to be present in outdoor systems (pasture). The management of severe EAS essentially requires environmental control to ensure improvement of lung function and in some cases medical treatment with corticosteroids and bronchodilators to ameliorate the clinical signs of airway inflammation and bronchospasm. Considering the clinical importance of this syndrome, the dissertation focuses on further contributing to scientific knowledge of severe EAS. As such, we investigated the influence of lung function tests on the diagnosis and staging of the disease and developed a staging method using only portable equipment, which has the potential of being used in equine ambulatory practice. We also investigated the relation between severe EAS and resistance to gastrointestinal parasites, which had not been, to the author’s knowledge, previously reported in the Lusitano breed horses. This association has been reported in other equine breeds with severe EAS or with other multiple hypersensitivities (MHS). Lastly, because allergen avoidance is fundamental for the remission of severe EAS we examined owner compliance to a set of recommended guidelines for environmental management.
RESUMO - A síndrome de asma equina (SAE) grave é uma doença respiratória crónica, recorrente e altamente prevalente em animais adultos, estando associada à domesticação dos equinos. Devido à sua natureza insidiosa, o tratamento é muitas vezes frustrante, originando perdas económicas significantes. Quando expostos a ambientes com elevadas concentrações de partículas respiráveis, tais como esporos de fungos, ácaros, endotoxinas, pólen e outras partículas antigénicas, os animais geneticamente suscetíveis desenvolvem inflamação, hiper-reactividade e obstrução das vias aéreas. As concentrações de partículas respiráveis elevadas encontram-se normalmente presentes em sistemas de estabulação de equinos tradicionais, enquanto que em sistemas em extensivo (pastagem) estas concentrações tendem a ser menores. Assim, no maneio da SAE grave é essencial o controlo ambiental de modo a assegurar a melhoria da função pulmonar e em alguns casos o tratamento médico com corticosteroides e broncodilatadores para reduzir os sinais clínicos de inflamação das vias aéreas e broncospasmo. Tendo em conta a importância clínica desta síndrome, esta dissertação tem por objetivo contribuir para o conhecimento científico da SAE grave. Assim sendo, investigámos a influencia dos testes de função pulmonar no diagnóstico e estadiamento da doença e desenvolvemos um método de estadiamento, utilizando apenas equipamento portátil, o qual poderá ser utilizado na clínica em regime de ambulatório. Ainda, investigámos a relação entre SAE grave e a resistência a parasitas gastrointestinais, a qual até à data ainda não havia sido reportada em cavalos Puro Sangue Lusitanos. Esta associação foi, contudo, descrita em equinos de outras raças diagnosticados com SAE grave ou outras hipersensibilidades múltiplas. Por fim, considerando que a remoção de aeroalérgenos é fundamental para a remissão da SAE grave, procurámos avaliar a complacência dos donos dos animais asmáticos a um conjunto de recomendações de maneio ambiental.
CIISA through the project INOV CIISA 8.
N/A
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Balan, Ioan Iulia-Cristina. "Diagnostic de l'asthme chez l'enfant par la réversibilité de l'obstruction bronchique." Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0132/document.
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Des techniques d’exploration de la fonction respiratoire nécessitant une coopération minimale, réalisables en ventilation spontanée, sans anesthésie, sont nécessaires chez les jeunes enfants asthmatiques. De telles méthodes sont la mesure de l’impédance respiratoire par la technique des oscillations forcées, la mesure de la résistance spécifique des voies aériennes par pléthysmographie ou la capnographie qui mesure la concentration de CO2 dans le gaz expiré. L’objectif principal de travail a été l’amélioration du diagnostic de l’asthme infantile en utilisant des études cliniques et fondamentales. Une étude clinique incluant des enfants asthmatiques et témoins a montré que la spécificité de la résistance est améliorée en expiration par rapport à l’inspiration du au fait que la fermeture de la glotte à l’expiration est proportionnelle au degré de l’obstruction bronchique. Une autre étude a démontré que le diagnostic de l’asthme est amélioré par le calcul des variations d’admittance respiratoire à un bronchodilatateur, ce calcul n’étant pas influencé par l’artefact des voies aériennes supérieures. Une étude a montré que la mesure de la résistance spécifique des voies aériennes en ventilation spontanée est surestimée par rapport à la mesure en halètement. La capnographie est une méthode noninvasive qui donne des renseignements sur l’inhomogénéité de la ventilation pendant une obstruction bronchique aigue. Toutefois, elle peut être limitée chez le jeune enfant par une fréquence ventilatoire élevée. Une étude expérimentale a été menée chez le lapin pour valider les indices capnographiques à différentes fréquences ventilatoires pour identifier la présence d’une obstruction aigueShorter lung function testing methods are needed in young asthmatic children, requiring minimal cooperation, performed in spontaneous breathing, without anaesthesia. Such methods are measurement of respiratory impedance by forced oscillations technique, measurement of specific airway resistance by plethysmography or capnography, measurement of CO2 concentration in expired air. The main objective of this work was to improve pediatric asthma diagnosis by using clinical and experimental studies. A study including asthmatic and control children showed that the specificity of resistance was improved in expiration compared to inspiration due to the fact that the glottis closure during expiration was proportional to the degree of airway obstruction. Another clinical study demonstrated that asthma diagnosis was improved by computation of respiratory admittance response to a bronchodilator because this computation is not affected by upper airways artifact. A study showed that specific airway resistance measured during spontaneous breathing was overestimated compared to panting metthod. Capnography is a non invasive technique. The shape of the expired CO2 time course is altered by the non homogenous distribution of ventilation resulting from bronchoconstriction. But its clinical usefulness in young children may be limited by the relatively high respiratory rate. An experimental study was conducted in rabbits to validate capnogram shape indices at different rates of breathing during airway constriction by methacholine. The indices have detected the acute airway obstruction even at high frequencies, frequencies usually presented by infants during an acute bronchoconstriction
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Silva, Ronaldo Aparecido da. "Estudo dos mecanismos induzidos pelo treinamento físico aeróbico ao longo do tempo na inflamação pulmonar e no remodelamento brônquico em um modelo murino de asma." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-01112013-105844/.
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O treinamento aeróbico (TA) traz benefícios para os asmáticos, porém os mecanismos antiinflamatórios não são conhecidos. Estudos experimentais de asma têm mostrado que o TA reduz a inflamação pulmonar alérgica crônica (IPAC) e a reposta Th2, no entanto, nenhum estudo explicou quando os efeitos protetores são iniciados e qual é a principal via anti-inflamatória desencadeada. Objetivo: Avaliar o efeito do TA ao longo do tempo em um modelo murino de asma visando identificar quando são iniciados os efeitos anti-inflamatórios e a reversão do remodelamento brônquico (RB). Métodos: BALB/c (160 animais) foram divididos em 4 grupos: Controle (CT): não induzidos à IPAC e não treinados; Treinamento Aeróbico (TA): não induzidos à IPAC e treinados; OVA: induzidos à IPAC e não treinados; OVA+TA: induzidos à IPAC e treinados. Em seguida foram criados outros subgrupos 1, 3, 7, 15 e 30 dias de TA, ou seja, cada grupo foi repetidos 5 vezes para investigação do efeito do TA ao longo do tempo. Os grupos OVA foram sensibilizados com i.p. (OVA+HidroxAlum), após foram induzidos à IPAC com aerosol de OVA (1-3%) iniciado no dia 21 (3 x semana; 30 min./sessão). A adaptação ao TA foi realizada entre os dias 21 a 23, no dia 25 foi realizado o teste físico, no dia 28 o TA foi iniciado (50% intensidade, frequência 5 x, por 4 semanas). Vinte quatro horas da ultima sessão de TA (1, 3, 7, 15 e 30 dias) os animas foram anestesiados, eutanizados e coletados o lavado broncoalveolar (LBA) (contagem celular total e diferencial), sangue para quantificação das imunoglobulinas (IgE e IgG1) por técnica de reação de anafilaxia cutânea passiva (PCA), o tecido pulmonar para avaliação dos mediadores: IL-4, IL-5, eotaxina, RANTES, ICAM-1, VCAM-1, TGF-b, VEGF, Osteopontina (OPN), NF-kB, FOXP3, receptor de glicocorticóide (RG) e anti-inflamatórias IL-10 e IL-1ra (imunohistoquímica e quantificação por morfometria) e foi coletado também o músculo quadríceps para avaliação da produção das miocinas (IL-10, IL-1ra e IL-6) (imunohistoquímica e quantificado por análise de imagem). O RB (músculo liso, epitélio, deposições das fibras de colágeno e elástica e produção de muco) também foi avaliado por análise de imagem. Resultados: Não foi observada produção das miocinas (p>0,05). Os níveis de IgE, IgG1, migração celular, produção dos mediadores inflamatórios e o RB foram aumentados nos grupos OVA (p<0,05), que ainda mostraram redução da produção do RG (p<0,05). O TA aumentou o RG no músculo liso das vias aéreas, as produções de IL-10 e IL- 1ra aumentaram a partir do 7º dia por células peribrônquicas, ao mesmo tempo que foram reduzidos o NF-kB, IL-4, IL-5, eotaxina, RANTES, ICAM-1, VCAM-1, VEGF, eosinófilos no LBA e foram revertidos o espessamento do músculo liso, do epitélio e as deposições de fibras de colágeno (p<0,05). Curiosamente, a diminuição de TFG-b ocorreu após o 3º dia, enquanto OPN, elástica e muco ocorreram após 15 dias de TA, enquanto IgE, IgG1 e neutrófilos apenas foram reduzidas ao final de 30 dias (p<0,05). Conclusão: A partir do 3º dia do TA foi iniciado o mecanismo anti-inflamatório pelo aumento do RG no músculo liso das vias aéreas, seguido pelo aumento de IL-10 e IL-1ra e pela redução de NF-kB a partir do 7º dia do TA, efeitos que reverteram a inflamação alérgica crônica e o RBThe aerobic training (AT) promotes benefits for asthmatics, but the anti-inflammatory mechanisms are not known. Experimental studies of asthma have shown that AT reduces the pulmonary allergic chronic inflammation (PACI) and response Th2, however no study has ever explained when the protective effects are initiated and which is the main anti-inflammatory pathway triggered. Aim: To evaluate the effect of AT over time in a murine model of asthma to identify when the anti-inflammatory effects is started and reverse bronchial remodeling (BR). Methods: BALB/c (160 mice) were divided into 4 groups: Control (CT): not induced to PACI and untrained; Aerobic Training (TA): not induced to PACI and trained; OVA: induced to PACI and untrained; OVA + TA: induced to PACI and trained. After that were created others subgroups 1, 3, 7, 15 and 30 days AT, that is, each group was repeated 5 times to investigate the effect of AT over time. The OVA groups were sensitized with i.p. OVA (OVA+AlumHidrox), and then the mice were induced after the PACI with aerosol of OVA (1-3%) started on the 21st day (3 x week, 30 min./Session). Adaptation to TA was held between 21-23, on the 25th day the physical test was performed, and on day 28 AT was begun (50% intensity, frequency x 5 for 4 weeks). Twenty four hours of the after last session of AT (1, 3, 7, 15 and 30 days) the mice were anesthetized, euthanized and the bronchoalveolar lavage fluid was collected (BALF) (Total and differential cell count) and blood was used to quantify immunoglobulins (IgE and IgG1) by passive cutaneous anaphylaxis reaction (PCA) technique, the pulmonary tissue was removed and used to evaluate the mediators IL-4, IL-5, eotaxin, RANTES, ICAM-1, VCAM-1, TGF-b, VEGF, osteopontin (OPN), NF-kB, FOXP3, glucocorticoid receptor (GR), and antiinflammatory IL-10 and IL-1ra (immunohistochemistry and quantified by morphometry), was also the quadriceps muscle to assess the expression of myokines (IL-10, IL-1ra and IL-6) (by immunohistochemistry and image analyses). The BR (smooth muscle, epithelium, collagen and elastic fibers deposition, and mucus production) was also evaluated by image analysis. Results: It was not observed any production of myokines (p>0.05). The levels of IgE and IgG1, cell migration, production of inflammatory mediators, and the BR were increased in the OVA groups (p<0.05); that still showed a decreased production of the GR (p<0.05). The AT promoted an increase of GR in the airway smooth muscle from the 3rd day, the production of IL-10 and IL- 1ra were increased from day 7 for cells peribronchial, while NF-kB, IL-4, IL-5, eotaxin, RANTES, ICAM-1, VCAM-1, VEGF, eosinophil counting in BALF were reduced, and reversed the smooth muscle thickening, epithelium and deposition of collagen fibers too (p<0.05). Interestingly, the decreasing of TGF-b occurred in the 3rd day, and OPN, elastic fibers, mucus occurred after 15 days of AT, while IgE and IgG1, and neutrophils were reduced only after 30 days (p<0.05). Conclusion: The anti-inflammatory mechanism by increasing the GR on the smooth muscle of the airways was initiated from the 3rd day of the AT, followed by an increase of IL-10 and IL-1ra and a reduction of NF-kB from the 7th day of the AT, reversed the effects of chronic allergic inflammation and bronchial remodeling
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Everaere, Laëtitia. "Rôle des cellules lymphoïdes dans l’exacerbation de l’asthme par des co-facteurs environnementaux." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S001.
Full textAbstract:
La prévalence de l’asthme a doublé dans les pays occidentaux depuis environ 1980. Une croissance alarmante qui fait face aux changements de mode de vie : hygiène (l’exposition à des agents infectieux), alimentation, ou encore pollution. Ces éléments sont des co-facteurs de risque, potentiellement responsables de l’installation de l’asthme ou de son aggravation. Cependant aucun mécanisme clair n’est déterminé à ce jour. Ce travail de thèse s’est focalisé sur le rôle des protagonistes centraux de la réponse immune, les populations lymphoïdes innées et adaptatives, dans l’exacerbation de l’asthme par ces différents co-facteurs. L’obésité est associée à une prévalence accrue d’asthme. Récemment, les cellules lymphoïdes innées (ILC) ont été impliquées dans ces pathologies. L’axe principal de mon travail a été de caractériser la contribution des lymphocytes T comparativement aux ILC dans un modèle murin d’exacerbation de l’asthme induit par des allergènes d’acariens liée à l'obésité. Un régime riche en graisse aboutit à l’exacerbation des caractéristiques de l’asthme, incluant l’hyperréactivité bronchique, la réponse humorale, le recrutement des éosinophiles circulants et tissulaires. Parallèlement à une exacerbation des profils pulmonaires Th2 et Th17, la quantité des ILC2 et ILC3 activées est amplifiée chez les souris asthmatiques obèses et associée à une augmentation de l’expression de l’IL-33, l’IL-1β et une diminution des marqueurs des ILC dans le tissu adipeux viscéral. La déplétion des ILC dans ce modèle a confirmé leur implication dans l’exacerbation de l’asthme chez les souris obèses, notamment via une activation des profils Th2 et Th17. Parallèlement, nous avons évalué l’incidence des HAP, polluants provenant d’échappement diesel, en mesurant les caractéristiques moléculaires de l’asthme sévère. Parmi les cellules mononucléaires du sang activées, les particules d’échappement du diesel (DEP)-HAP et celles du benzo[a]pyrène (B[a]P) induisent une augmentation de la production d’IL-22 plus élevée chez les sujets allergiques asthmatiques (AA), et une diminution de l’IL-17A. Cette production d’IL-22 est majoritairement issue des cellules Th22, et son mécanisme d’induction est principalement dépendant de l’AhR sous l’effet des DEP-HAP contrairement au B[a]P. Enfin, nous avons étudié l’impact des infections. L’activation de NOD1 des cellules dendritiques (DC) humaines, indépendamment de l’allergène, promeut un profil Th2, induit préférentiellement la production de CCL17 chez un patient asthmatique, leur maturation et perturbe la production de CCL22 et de l’IL-10. Chez la souris, l’activation systémique de NOD1 exacerbe l’asthme allergique, via l’augmentation de la réponse pulmonaire de type Th2 dépendamment de CCL17.Dans une autre étude, la costimulation de DC immatures humaines par un allergène de chien et le ligand de TLR3 ou TLR9 accentue la différentiation, l’expression de marqueurs d’activation et la production cytokinique des DC, avec l’induction d’un profil Th22/Th1 chez les sujets saints, contrairement à un profil Th22/Th17/Th2 chez les patients AA. Cette activation spécifique des DC, induite par la costimulation chez un patient AA, provoque la sécrétion d’IL-17A, IL-17F et d’IL-13, ainsi qu’une amplification de la production d’IL-22 par les lymphocytes Th22. Tout ceci suggère que la costimulation par certains allergènes et/ou pathogènes peut induire une réponse Th22 et Th17 chez les sujets asthmatiques, et contribuerait à la sévérité de certains asthmes.L'ensemble de ces travaux ont permis d’établir de nouvelles appréhensions des déterminants potentiels dans l’asthme ainsi que de nouvelles notions des mécanismes moléculaires et cellulaires gouvernant la réponse immuneThe prevalence of asthma has increased twice in Western countries since about 1980. An alarming growth which correlates with lifestyle changes: sanitary conditions (exposure to infectious agents), nutrition, or pollution. These elements are risk co-factors, involved in asthma development or aggravation. However, no clear mechanism is determined to date. This work focused on the role of central players in the immune response, the innate and adaptive lymphoid populations in asthma exacerbation by these different cofactors.Obesity is associated with an increased prevalence of asthma. Recently, the innate lymphoid cells (ILC) were involved in these 2 pathologies. The main focus of my work was to characterize the T cells compared to ILC contribution in a murine model of asthma exacerbation induced by mite allergens linked to obesity. A high fat diet leads to the exacerbation of the main asthma features, including bronchial hyperresponsiveness, humoral response, recruitment of circulating and tissue eosinophils. In parallel to the exacerbation of Th2 and Th17 profiles, the amount of activated ILC2 and ILC3 is amplified in the lung of obese asthmatic mice and associated with increased expression of IL-33, IL-1β and reduced ILC markers in visceral adipose tissue. ILC depletion in this model confirmed their involvement in asthma exacerbation in obese mice, especially through Th2 and Th17 profiles activation.On the other hand, we evaluated the impact of PAH, pollutants from diesel exhaust, by monitoring the molecular characteristics of severe asthma. Among the activated blood mononuclear cells, diesel exhaust particles (DEP)-PAH and those of benzo[a]pyrene (B[a]P) enhance IL-22 production in asthmatic allergic patients (AA), and decrease IL-17A. Th22 cells are the major source of this IL-22 production and its induction mechanism is mainly dependent on AhR under the effect of DEP-PAH contrary to B[a]P.Finally, we investigated the impact of infections. NOD1 priming of human dendritic cells (DC), independently of the allergen presentation, promoted a Th2 polarization profile which involved the production of both CCL17 and CCL22 in nonallergic subjects but only CCL17 in allergic patients. Moreover, NOD1-primed DC from allergic donors exhibited enhanced maturation that led to abnormal CCL22 and IL-10. In mice, systemic NOD1 activation exacerbates allergic asthma, via the increase in pulmonary Th2 response depending on CCL17.In another study, the costimulation of human immature DC, by dog allergen and TLR3 or TLR9 ligands, increases the DC differentiation, expression of activation markers and cytokine production, with the induction of a Th22/Th1 profile in healthy subjects, unlike a Th22/Th17/Th2 profile in AA patients. This specific DC activation, induced by costimulation in AA patients, leads to the IL-17A, IL-17F and IL-13 secretion, as well as the amplification of IL-22 production by Th22 cells. All this suggests that costimulation by certain allergens and/or pathogens can induce Th22 and Th17 response in asthmatic subjects, and may contribute to the severity of some asthma cases.Taken together, the results presented in this work establish new apprehensions of potential asthma determinants, as well as new concepts of molecular and cellular mechanisms underlying the immune response
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Irusen, Elvis Malcolm. "Glucocorticosteroid receptor characteristics of peripheral blood mononuclear cells in oral steroid dependent asthma : utilization of an in vitro model of steroid resistant asthma to investigate mechanisms of resistance and functional consequences of altered receptor affinity." Thesis, 2007. http://hdl.handle.net/10413/2527.
Full textAbstract:
Background: Although glucocorticoids are the most effective treatment for
asthma, some patients show a poor response. In such patients with steroid resistant asthma, this has been ascribed to altered glucocorticoid receptor (GR) ligand-binding affinity induced by IL-2 combined with IL-4 or IL-13
alone- all of which can also modulate glucocorticoid function in vitro.
Objective: We sought to assess the ligand-binding affinity in a distinct group
of oral steroid-dependent asthmatic subjects and examine the mechanisms by
which IL-2 and IL-4 (or IL-13) modify the ligand-binding affinity of the GR.
Methods: Using dexamethasone-binding assays, we examined PBMCs ex
vivo from healthy subjects, subjects with controlled asthma, and oral steroiddependent
subjects with severe asthma. In addition, IL-2 and IL-4 were used to alter GR affinity in vitro. We used mediators or inhibitors of signal
transduction to investigate the mechanisms of resistance. We also determined
cytokine production of PBMC's by means of ELISA.
Results: GR ligand-binding affinity was significantly reduced in the nucleus but not in the cytoplasm of oral steroid-dependent asthmatic subjects compared with that seen in steroid-sensitive and healthy subjects (dissociation
constant, 41.37 ± 17.83 vs. 25.36 ± 2.63 nmol/L vs. 9.40 ± 4.01 nmol/L,
respectively [p<.05 for both in comparison to normals] ).
This difference in ligand-binding affinity could be mimicked by IL-2 and
IL-4 co-treatment and was blocked by the p38 mitogen-activated protein
kinase (MAPK) inhibitor SB203580. PBMC's rendered resistant in vitro
demonstrated lower IL-10 and increased GM-CSF production following LPS
or PMA & PHA stimulation compared to cells with normal GR affinity.
Resistant cells also showed reduced dexamethasone repression of LPSstimulated
IL-10 release. These effects were also reversed by SB203580.
Inhibition of the ERK MAPK pathway by PD098059 (10 mol/L),
phosphoinositol 3 kinase by wortmannin (5 nmol/L) or treatment with IL-10
(10 ng/mL) failed to modulate the effect of IL-2 and IL-4 on receptor affinity.
Ro318220 (10 nmol/L), a specific protein kinase C inhibitor and theophylline,
similarly, had no effect on affinity.
Conclusion: GR ligand binding affinity is tiered; compared to normal
subjects; steroid responsive asthmatics have a mild reduction in ligand binding whereas oral steroid dependent asthmatics have greater reductions.
When mononuclear cells are rendered resistant in vitro, cytokine production
(low IL-10 and high GM-CSF) favours a pro-inflammatory state. Our data do
not support the ERK MAPK, phosphoinositol 3 kinase, protein kinase C
pathways in steroid resistance. Treatment with IL-10 and theophylline also
failed to modulate the effect of IL-2 and IL-4 on receptor affinity. However, P38 MAPK inhibitors may have potential in reversing glucocorticoid
insensitivity and re-establishing the beneficial effects of glucocorticoids in patients with severe asthma.Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2007.
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Saurek-Aleksandrovska, Natalija. "Association between insulin resistance, metabolic syndrome, asthma and the other asthma phenotypes." 2013. http://hdl.handle.net/1993/21618.
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Herbert, Cristan Medical Sciences Faculty of Medicine UNSW. "Effects of glucocorticoid and phosphodiesterase-4 inhibitor therapy in a mouse model of chronic asthma." 2007. http://handle.unsw.edu.au/1959.4/40535.
Full textAbstract:
Asthma is a chronic inflammatory disease of the airways. Using a murine model which replicates many characteristic features of human asthma, this study evaluated the effects of treatment with anti-inflammatory drugs on the lesions of chronic asthma, and investigated potential underlying molecular mechanisms. Treatment with dexamethasone, a glucocorticoid, was compared with roflumilast, a novel phosphodiesterase-4 (PDE4) inhibitor. BALB/c mice sensitised to ovalbumin were challenged with a low mass concentration of aerosolised antigen for 30 min/day, 3 days/week for 6 weeks. In weeks 5 and 6, groups of animals were treated with either dexamethasone or roflumilast. Assessment included changes in acute-on-chronic inflammation, structural remodelling of the airways and airway hyper-responsiveness to a bronchoconstrictor stimulus. These were correlated with the expression of pro-inflammatory cytokines and growth factors. Compared to vehicle-treated control animals, dexamethasone- and roflumilast-treated mice exhibited reduced accumulation of intra-epithelial eosinophils and chronic inflammatory cells, including CD3+ T-lymphocytes in the airways. Similarly, both drugs inhibited subepithelial fibrosis and airway epithelial thickening, although only dexamethasone inhibited goblet cell hyperplasia/metaplasia. Airway hyper-reactivity was not diminished by either drug. Both treatments suppressed production of Th2 cytokines by ovalbumin-restimulated peribronchial lymph node cells. In selectively dissected airway tissue from vehicletreated animals, increased expression of mRNA for several pro-inflammatory cytokines (TNF-α, GM-CSF, IL-6) and cytokines characteristic of Th1 (IFN-γ), Th2 (IL-5, IL-13)and Th17 (IL-17A) cells was demonstrated using real-time PCR. Enhanced expression of growth factors (TGF-β1 and FGF-2) was also demonstrated in airway epithelium isolated by laser capture microdissection. Interestingly, whereas treatment with dexamethasone significantly inhibited expression of mRNA for all of the inflammationrelated cytokines examined, roflumilast inhibited only IL-17A, TNF-α, GM-CSF and IL-6. Both drugs inhibited mRNA expression of growth factors by epithelial cells. Because roflumilast was as effective as dexamethasone in suppressing inflammation and most changes of remodelling, the selective suppression of IL-17A, TNF-α, GM-CSF and IL-6 suggests that these mediators, or the cells that produce them, may have critical roles in pathogenesis. Furthermore, they may be particularly appropriate therapeutic targets in chronic asthma.
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Klaßen, Carina. "Airway Epithelial Cells as Targets of Glucocorticoid Therapy in Inflammatory Lung Diseases." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3DB4-1.
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Williams, Deon. "Effects of -tocopherol supplementation on dexamethasone-induced insulin resistance." Master's thesis, 2010. http://hdl.handle.net/10048/1372.
Full textAbstract:
This study aimed to examine potential mechanisms for glucocorticoid (GC)-induced decreases in glucose clearance, and to determine if a reduction in oxidative stress load via dietary pre-treatment with an antioxidant-rich diet has a positive net effect on glucose tolerance following a sub-chronic treatment with the GC analogue dexamethasone (DEX). Rats fed a diet supplemented with 700IU of -tocopherol for two weeks had improved glucose clearance after five days of DEX-treatment relative to unsupplemented rats as well as decreased markers of oxidative stress. Following an intraperitoneal bolus of insulin, phosphorylation of AMP activated protein kinase (AMPK) was preserved in the supplemented groups despite no significant differences in upstream insulin signalling cascade intermediates between DEX-treated groups. This was corroborated by a similar increase (p<0.05) in phosphorylation of the downstream AMPK substrate acetyl CoA carboxylase. This study demonstrated that -tocopherol supplementation can attenuate GC-induced decreases in glucose clearance in an AMPK-dependent manner.Nutrition and Metabolism
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Pinkerton, James. "Elucidating the mechanisms of steroid-resistant asthma." Thesis, 2018. http://hdl.handle.net/1959.13/1383707.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)Severe, steroid-resistant (SSR) asthma is of considerable clinical and economic significance as affected individuals do not respond to mainstay corticosteroid therapies. Patients with SSR asthma experience more frequent exacerbations of disease, are more likely to require hospitalisation and have a poor quality of life. Improved therapies are urgently required for SSR asthma, however, progress in this area has been hampered by a lack of understanding of the pathological processes that underpin disease. The major obstacle to understanding the processes that drive SSR asthma is that there are several subsets of the disease characterised by different inflammatory and immunological phenotypes. This heterogeneity disease makes pinpointing the key processes that underpin disease extremely difficult in humans. To help understand the mechanisms that underpin SSR asthma, we have developed three unique infection-induced models of SSR asthma. As part of my thesis, I have also developed a high fat diet-induced, obesity-associated SSR asthma. Together, all four models recapitulate the key features of a number of different subsets/clusters of SSR asthma in the clinic and represent useful tools to understand subset-specific and universal factors/processes that underpin of disease and test novel therapies that target the factors/processes identified. The overarching aim of my PhD is to utilise these models to elucidate novel mechanisms that may underpin SSR asthma and to determine whether targeting these mechanisms with therapeutic interventions can suppress disease, where steroids are not effective. My PhD was divided into three major aims that have focused on discovering novel factors associated with disease and assessing the roles played by known associative factors potentially drive steroid resistance. Firstly, I conducted array analyses on whole lung tissue from our three models of infection-induced SSR asthma, that represent different inflammatory and immune subsets observed in the clinic, to identify factors that are universally dysregulated in disease. I identified 11 universally dysregulated genes, most of which have not been previously recognised in SSR asthma (chapter 2). I then showed the functional role that one of these factors may being playing in driving SSR asthma (chapter 2). Secondly, I have identified dysregulated antioxidant responses as playing a critical role in our Chlamydia-induced model of SSR asthma and show that restoration of antioxidant responses may be a beneficial adjunct therapy for steroid-resistant disease (chapter 3). Lastly, I have developed a new murine model of high fat diet (HFD)-induced obesity that induces SSR allergic airways disease (AAD) (chapter 4). I used this model to identify a previously unrecognised role for HFD/obesity-induced, NLRP3 inflammasome-mediated responses in the lung the development of steroid-resistant airways hyper-responsiveness (AHR). I also show that HFD/obesity induced NLRP3 inflammasome responses in the lung may be therapeutically targeted for the treatment of HFD/obesity-associated, steroid-resistant AHR. Together the findings from my PhD studies inform new mechanisms and pathways that may underpin SSR asthma in the clinical setting and highlight potential therapeutic targets and strategies for the treatment of disease. The development of a representative obesity-induced model of SSR asthma will be a useful tool for future studies that aim to identify mechanisms and treatment strategies for obese SSR asthmatics.
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Li, Jingjing. "Respiratory innate immune factors regulate steroid-resistant airway hyperreactivity and asthma." Thesis, 2014. http://hdl.handle.net/1959.13/1045322.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)Asthma is a chronic inflammatory disease of the airways and a combination of genetic and environmental factors underpin the pathogenesis. The clinical symptoms of asthmatics most mild to moderate, allergic asthma patients can be effectively managed by combination therapy with broad-spectrum anti-inflammatory agents and bronchodilators (typically inhaled glucocorticoids and long acting β-agonists). Indeed, glucocorticoids remain the forefront therapeutical approaches for the treatment of asthma. However, 5-10% of asthmatics who have severe asthma do not respond to treatment, and these patients account for almost 50% of asthma-related healthcare costs. Thus it is essential to understand the pathogenesis of steroid resistance in severe asthma for the development of more efficient therapies for those patients. With well-established animal models of steroid resistant airway hyper-responsiveness (AHR, a hallmark feature of asthma) and in vitro culture systems of pulmonary macrophages, the underlying mechanisms regulating steroid resistance and exacerbation of asthma have been thoroughly investigated, particularly on the causative roles of innate immune factors. This thesis consists of three publications. The first publication identifies changes in the expression of key innate immune molecules and their signalling pathways in a mouse model of steroid-resistant AHR and demonstrates the central role of pulmonary macrophages in the induction of steroid-resistant AHR The second publication investigates the expression of olfactory receptors in the respiratory system and on immune cells in response to innate immune activation, and identifies a potential role of olfactory receptors in regulating the function of pulmonary macrophages. The final publication discusses the modulation of small non-coding RNAs, microRNA, expression by innate immune activation in a steroid-resistant mouse model of asthma and evaluates the role of key microRNAs involved in the induction of steroid-resistant AHR by regulating the activity of a critical phosphatase, protein phosphatase-2A, which further affected the function of glucocorticoid.
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Hennig, Heike. "Untersuchungen zu molekularen Mechanismen der Glucocorticoid-Resistenz bei Akuter Lymphatischer Leukämie (ALL)." Doctoral thesis, 2003. http://hdl.handle.net/11858/00-1735-0000-0006-AD8E-E.
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Hadjigol, Sara. "Understanding the mechanisms of bacterial-induced exacerbation of allergic airways disease in a mouse model." Thesis, 2017. http://hdl.handle.net/1959.13/1349583.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)Activation of innate immune responses in individuals with asthma by respiratory viral and bacterial infections or colonization with pathogenic bacteria can cause disease exacerbation. Exacerbations have a negative impact on quality of life and are characterised by persistent airway inflammation, worsening of disease symptoms and poor responsiveness to standard corticosteroid therapy. How activation of innate host defence pathways by bacterial infection triggers steroid-resistant inflammatory pathways and disease exacerbation is poorly understood. Better disease models are urgently required to identify mechanisms underlying disease exacerbation. We hypothesised that bacterial infection (mimicked by lipopolysaccharide (LPS) exposure) would exacerbate pre-existing allergic airways disease (AAD) in a mouse model, causing steroid-resistant airways inflammation and airway hyperresponsiveness (AHR). Mice were initially sensitized and subsequently challenged with nebulised ovalbumin (OVA) to induce AAD. LPS was then administered into the lung, in the presence or absence of dexamethasone (DEX) to assess steroid sensitivity. Disease outcomes were assessed by quantifying lung function (airways hyperresponsiveness; AHR), inflammatory cell infiltration, tissue cytokine levels and microarray profiling. LPS administration induced steroid-resistant AHR and increased inflammatory cytokine expression (including interleukin (IL)-27, interferon (IFN)γ, macrophage inflammatory protein (MIP)-1α and tumour necrosis factor α (TNFα)), while CD4+ T-helper 2 (Th2) cytokines (IL-5 and IL-13) were not altered compared to OVA-treated mice. Neutrophil and macrophage numbers were also increased in the bronchoalveolar fluid (BALF) following LPS administration. Targeted depletion of alveolar macrophages with 2-chloroadenosine (2-CA) significantly suppressed AHR. Further, IL-13 was required for exacerbation, as LPS failed to exacerbate AHR in IL-13 deficient mice or following administration of IL-13 blocking antibodies. Microarray profiling of lung samples revealed that microRNA (miR)-135b-5p expression was markedly increased following LPS administration in mice with pre-existing AAD and expression was only partially suppressed by corticosteroid treatment. Inhibition of miR-135b-5p function by antagomir treatment suppressed LPS-induced exacerbations AHR and markedly reduced inflammatory cell infiltration. In summary, we developed a novel mouse model of LPS-induced steroid-resistant exacerbation of AAD, which mimic critical features of infection-induced exacerbation of asthma. Our findings highlight key roles for pulmonary macrophages, IL-13 and miR-135b-5p in the development of disease symptoms. Targeting these pathways may be a useful treatment for acute bacterial-induced exacerbation of asthma.
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Kim, Richard Yong Hoon. "Investigation of the mechanisms of respiratory infection-induced lung disease." Thesis, 2015. http://hdl.handle.net/1959.13/1060846.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)Chlamydia respiratory infections have been widely linked with the development and exacerbation of asthma, particularly more severe forms of asthma, in both children and adults. Murine models of Chlamydia respiratory infection and AAD were used to investigate the mechanisms that underpin the association between infection and asthma. We have made important and novel observations that demonstrate how neonatal Chlamydia infection results in chronic lung disease. We show that neonatal Chlamydia infection induces a group of 5 miRNAs (miR-155, miR-21, miR-223, miR-146b and miR-203) during infection and that the therapeutic inhibition of each miRNA can prevent the development of key disease features, including lung inflammation and histopathology, persistent AHR, emphysema-like alveolar enlargement and increased severity of AAD in later life. We have also made important and novel observations that further our understanding of the mechanisms that underpin the association between Chlamydia respiratory infection and severe, steroid-insensitive asthma. We demonstrate that Chlamydia respiratory infection in established AAD induces a miR-21/PI3K/pAkt/HDAC2 signalling axis to promote severe, steroid-insensitive AAD. Importantly, the therapeutic inhibition of Chlamydia-induced miR-21 and/or PI3K signalling restores sensitivity to steroid treatment. Additionally, the therapeutic inhibition of miR-21 also suppresses the key features of Haemophilus respiratory infection-induced, severe, steroid-insensitive AAD. We also demonstrate that Chlamydia respiratory infection induces an NLRP3 inflammasome/Caspase-1/IL-1β signalling axis to promote severe, steroid-insensitive AAD. Importantly, the therapeutic inhibition of Chlamydia-induced NLRP3 inflammasome and/or Caspase-1 and/or IL-1β signalling restores sensitivity to steroid treatment. Furthermore, the therapeutic inhibition of each component of this axis also suppresses the key features of Haemophilus respiratory infection-induced, severe, steroid-insensitive AAD. Our studies significantly contribute to understanding the role of neonatal Chlamydia respiratory infection in the development of chronic lung disease and severe asthma in later life, and the roles of Chlamydia and Haemophilus respiratory infections in promoting severe, steroid-insensitive asthma. Importantly, our studies suggest that therapeutically targeting key Chlamydia and Haemophilus respiratory infection-induced factors in the lung may be effective for the prevention and/or treatment of severe asthma.
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Nguyen, Thi Hiep. "Modeling of respiratory syncytial virus-induced exacerbation of allergic airways disease." Thesis, 2017. http://hdl.handle.net/1959.13/1337694.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)Asthma is a chronic inflammatory disorder of the airways characterised by clinical symptoms such as wheeze, shortness of breath, airflow obstruction, mucus hypersecretion and airway hyper-responsiveness (AHR). Numerous factors contribute to the pathogenesis of asthma, including respiratory infections, allergens, pollution and smoking. These factors can trigger asthma exacerbations, which are defined as a worsening of clinical symptoms. Asthma exacerbations are a major cause of hospitalisation and occur in all asthmatic patients regardless of disease severity. Although mild-to-moderate asthma can generally be well-controlled with glucocorticoid (GC) treatment, exacerbations are often difficult to treat and new effective approaches are needed. Viral respiratory infections, such as respiratory syncytial virus (RSV), are associated with exacerbations in patients with pre-existing asthma. Although allergic asthma is critically regulated by increased CD4+ T-helper (Th) type 2 (Th2) responses and type 2 innate lymphoid cells (ILC2s), viral infections are thought to exacerbate asthma by enhancing allergic inflammation and/or through activation of innate immune responses. Clinical studies have identified a complex range of immune responses during viral-induced exacerbations involving Th2, Th1 and Th17 responses, and activation of host innate immunity including macrophages. However, the disease mechanisms and the role of innate immune responses in particular, which underlie viral-induced exacerbations remain poorly understood. The aim of this PhD project was to establish a mouse model of RSV-induced exacerbations, which presents hallmark features of viral-induced exacerbations in humans. This model was then used to investigate the immunological mechanisms underpinning disease, and to identify new potential approaches for treatment. Chapter 2 describes the development and characterisation of our RSV-induced exacerbation model of AHR and airway inflammation in a mouse model of pre-existing allergic airways disease (AAD). Exacerbation was associated with activation of innate host immune responses. Notably, exacerbation only occurred on the background of AAD, indicating the importance of an underlying type 2 environment for pathogenesis. Further, RSV-induced exacerbation failed to respond to GC treatment. In this study, key functional roles for tumour necrosis factor-alpha (TNFα), monocyte chemoattractant protein (MCP)-1 and pulmonary macrophages in exacerbation were demonstrated through intervention studies. Further, increased TNFα and MCP-1 expression was observed in neutrophilic asthmatic patients, a subpopulation that often poorly respond to GC treatment. Chapter 3 investigated the role of the pro-inflammatory cytokines interferon-gamma (IFN-γ) and interleukin (IL)-27 as key regulators in the model of RSV-induced steroid-resistant exacerbation. RSV-induced exacerbation increased expression of IFN-γ and IL-27, which was resistant to GC treatment. Neutralisation of either IFN-γ or IL-27 completely suppressed RSV-induced AHR. This study further highlighted the role of these molecules in conjunction with macrophages in the induction of RSV-induced exacerbation. In Chapter 4, the effectiveness of a new anti-inflammatory bromodomain and extra terminal (BET) inhibitor (I-BET) was assessed for the suppression of steroid-resistant AHR. Two steroid-resistant airways disease models; a previously-described short-term model induced by IFN-γ and lipopolysaccharide (LPS) administration to the lung (two factors linked to steroid-resistant asthma) and our RSV-induced exacerbation model (Chapter 2) were used. I-BET treatment effectively suppressed AHR and airway inflammation in both models, by inhibiting the activation of pulmonary macrophages. These findings suggest that inhibition of BET proteins may be a novel therapeutic pathway to treat asthma exacerbations, by targeting macrophages. Thus these investigations indicate that in the context of underlying pre-existing allergic airways inflammation (found in asthma), RSV infection stimulates innate immune responses, increasing inflammation and AHR. In particular, key roles for TNFα, MCP-1, IFN-γ, IL-27 and pulmonary macrophages in the pathogenesis of RSV-induced exacerbation were demonstrated. Further, the new anti-inflammatory reagent, I-BET, was shown to significantly suppress all key features of RSV-induced steroid-resistant exacerbation (e.g inflammation and AHR) and IFN-γ/LPS-induced steroid-resistant AHR. These observations provide evidence for an important role of BET proteins in the regulation of steroid-resistant AHR and airway inflammation. Therefore, these studies provide evidence that targeting innate immune activation could be a therapeutic approach for the treatment of viral-induced asthma exacerbation.