Dissertations / Theses on the topic 'ST2 expression in asthma'
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1
Bradding, Peter. "Cytokine expression in allergic mucosal inflammation." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295929.
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Osman, Mustafa. "The expression of asthma in relation to sex and sex steroids from birth to adulthood." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25474.
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Stinson, Sally Elizabeth. "Exploring the expression and function of CRTh2 in asthma." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/31996.
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CRTh2 (DP2) is implicated in the pathogenesis of asthma; however, currently there is a lack of data describing the protein expression of CRTh2 in bronchial biopsies in asthma. This has limited the cell types that CRTh2 function has been explored within. A thorough understanding of CRTh2 expression within the airways and whether changes in receptor expression correlates with disease severity, may aid in the design of future CRTh2 antagonist clinical studies. This study aimed to investigate the expression of CRTh2 expression in bronchial biopsies of subjects with asthma and healthy controls. The novel finding that CRTh2 was expressed on bronchial epithelial cells in asthma prompted further investigation into the expression and activation of CRTh2 on bronchial epithelial cells in vitro, using the selective CRTh2 agonist 13, 14-dihydro-15-keto prostaglandin D2 (DK-PGD2) and the CRTh2 selective antagonist AZD6430. This study is the first to describe differential CRTh2 expression within bronchial tissue in asthma compared to healthy controls. The number of sub-mucosal CRTh2+ cells was found to be increased in asthma compared to healthy controls. CRTh2 was found to be expressed on the bronchial epithelium and its expression was decreased in asthma compared to healthy controls with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthma and related to decreased CRTh2 expression. DK-PGD2 promoted epithelial cell migration, and in air-liquid interface cultures increased the number of MUC5AC+ and involucrin+ cells, which were blocked with the CRTh2 antagonist, AZD6430. This study describes the novel findings that CRTh2 is expressed by the bronchial epithelium in both health and asthma, and its activation drives epithelial differentiation. These data suggests that CRTh2 could contribute to airway remodelling in asthma and this information may contribute to the understanding of the effects of CRTh2 antagonists in asthmatic patients.
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Seymour, Michelle L. "Expression of eicosanoid pathway enzymes in inflammatory cells." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310699.
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Kuitert, Lieske Meta Elizabeth. "Eicosanoid synthetic enzymes : aspects of regulation and expression in asthma." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248441.
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Konstantinidis, Athanasios. "Genetics and airway expression of interleukin-13 receptors in asthma." Thesis, University of Southampton, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418599.
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Cowburn, Andrew Stephen. "Regulation of eicosanoid enzyme expression in inflammatory leukocytes in asthma." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266655.
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Lacson, Ronilda, Michael Mbagwu, Hisham Yousif, and Lucila Ohno-Machado. "Assessing the quality of annotations in asthma gene expression experiments." BioMed Central, 2010. http://hdl.handle.net/10150/610165.
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BACKGROUND:The amount of data deposited in the Gene Expression Omnibus (GEO) has expanded significantly. It is important to ensure that these data are properly annotated with clinical data and descriptions of experimental conditions so that they can be useful for future analysis. This study assesses the adequacy of documented asthma markers in GEO. Three objective measures (coverage, consistency and association) were used for evaluation of annotations contained in 17 asthma studies.RESULTS:There were 918 asthma samples with 20,640 annotated markers. Of these markers, only 10,419 had documented values (50% coverage). In one study carefully examined for consistency, there were discrepancies in drug name usage, with brand name and generic name used in different sections to refer to the same drug. Annotated markers showed adequate association with other relevant variables (i.e. the use of medication only when its corresponding disease state was present).CONCLUSIONS:There is inadequate variable coverage within GEO and usage of terms lacks consistency. Association between relevant variables, however, was adequate.
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Tuttle, Camilla Susannah Laura. "The expression of HAT and HDAC enzymes in asthma airways." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/62873/1/Camilla_Tuttle_Thesis.pdf.
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Asthma is chronic inflammatory disease of the lower airways that is both, genetically inherited and environmentally influenced. This project investigated how molecular mechanisms known to be influenced both genetically and environmentally, contribute to the onset of asthma.
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Hillaby, Caroline Wendy. "Expression of phosphodiesterase isoenzymes in inflammatory cells in allergic airway disease." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370062.
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Vasavda, Nisha. "Steroid dependent asthma : gene expression changes in T-lymphocytes and functional consequences." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405899.
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Tajiri, Tomoko. "Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma." Kyoto University, 2014. http://hdl.handle.net/2433/185195.
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Glare, Eric M. 1965. "The application of competitive PCR technology to asthma research." Monash University, Dept. of Medicine, 2001. http://arrow.monash.edu.au/hdl/1959.1/7975.
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Saunders, Michael Anthony. "The expression, regulation and functional role of cyclooxygenase isoforms in human airway cells." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300789.
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Standring, Peter. "Class II Human Leukocyte Antigen gene polymorphisms, cell surface expression and immunoglobulin E mediated disease." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262910.
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Al-Ramli, Wisam. "Expression of Th-17 related cytokines (IL-17A and F) in severe asthma." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95068.
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Inflammation and airway remodelling are hallmarks of severe asthma pathology. Although severe asthma represents 10% of the asthmatic population, this subset of patients has greater morbidity, mortality and a disproportionate need for health care services. Severe asthma appears to have a different inflammatory pattern compared to mild and moderate asthma. There is an increase in neutrophil infiltration, upregulation of IL-8 and disregulation of Th-2 cytokines. IL-17A and F are two proinflammatory and profibrotic cytokines produced primarily by Th-17 cells. These cytokines can act on a broad range of cell types to induce cytokines, chemokines and metalloproteinases as well as have important roles in neutrophil activity. We hypothesize that IL-17A and F are expressed in asthmatic airways and are increased in severe disease. The objective of our study is to investigate the expression of IL-17A and F in biopsies of severe asthmatics, and compare them with moderate and mild asthmatics as well as control subjects and relate this expression to that of IL-8 and neutrophilia. The expression of IL-17A and F mRNA and protein was evaluated in bronchial biopsies using immunocytochemistry and real-time PCR. The expression of both IL-17A and F were shown to be increased in severe asthmatic airways compared to mild asthmatics and control subjects. IL-17A was mostly expressed in mononuclear cells present in the subepithelial tissue within clusters of inflammatory cells, whereas IL-17F was expressed not only in inflammatory cells but also in epithelial cells. This observation was confirmed using laser capture microdissection. Our results are consistent with the possible role of IL-17 family in steroid hyperresponsive disorders, including rheumatoid arthritis, psoriasis and refractory asthma. We suggest that both IL-17A and F contribute to severe asthma inflammatory and airway remodelling pathology. Our findings further the knowledge on severe asthma disease and open new options toLe processus inflammatoire et le remodelage des voies respiratoires sont typiquement liés à la pathologie de l'asthme réfractaire. Bien que l'asthme réfractaire n'affecte que 10% des asthmatiques, ce sous-groupe de patients est caractérisé par une plus grande morbidité, mortalité ainsi qu'un besoin disproportionné des services des soins de santé. Il semble que l'asthme réfractaire utilise un mécanisme d'inflammation distinct de celui associé à l'asthme léger et modéré. Il y a une augmentation de l'infiltration des neutrophiles, une régulation positive de l'IL-8 ainsi qu'une dérégulation des cytokines Th-2. Les cytokines IL-17A et F sont pro-inflammatoires, pro-fibrotiques et sont principalement produites par les cellules Th-17. Ces cytokines peuvent agir sur plusieurs types de cellules afin d'induire la production de cytokines, chémokines et métalloprotéinases. De plus, ces deux cytokines jouent un rôle prédominant dans l'activité des neutrophiles. Nous faisons l'hypothèse que l'IL-17A et F sont exprimées dans les voies respiratoires des asthmatiques et qu'elles sont augmentées dans l'asthme réfractaire. Cette étude a pour but d'investiguer l'expression de l'IL-17A et F sur biopsies provenant d'asthmatiques réfractaires et d'en faire la comparaison à celles provenant d'asthmatiques légers, modérés ainsi que de sujets sains et de relier cette expression à celle de l'IL-8 et de la neutrophilie. L'expression des ARNm et des protéines de l'IL-17A et F a été évaluée sur biopsies par immunocytochimie et real-time PCR'. Il a été démontré que l'expression de l'IL-17A et F est augmentée dans les voies aériennes des asthmatiques réfractaires en comparaison aux asthmatiques légers et sujets sains. L'IL-17A est principalement exprimée par les cellules mononucléaires des tissus des régions sous-épithéliales parmi les grappes de cellules inflammatoires. L'IL-17F n'est pas uniquement exprimée par les cellules inflammatoi
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Di, Candia Leonarda. "The expression and function of RAGE and HMGB1 in airway structural cells in asthma." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/32339.
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Asthma is characterised by airway hyperresponsiveness, airflow obstruction, chronic inflammation and airway remodelling, with an increase in airway smooth muscle (ASM) mass and contractility. ASM also releases mediators that support inflammation and remodelling. High-mobility group box 1 (HMGB1) is a nuclear protein that is released by damaged/stressed cells and activated immune cells. HMGB1 signals through pattern recognition receptors (PRRs) including the receptor for advanced glycosylation end products (RAGE) to promote inflammation and tissue repair. HMGB1 binding and function are governed by its redox state. Evidence suggests HMGB1 elevation in asthma; however, the redox state of airway HMGB1 is unknown. Moreover, the expression and role of RAGE in regulating airway mesenchymal cells are unknown. We aimed to investigate HMGB1 and RAGE expression in bronchial tissue; the redox form of sputum HMGB1; the expression and role of HMGB1 and RAGE in airway structural cells. HMGB1 was 3.5-fold higher in sputa of moderate-to-severe asthmatics (n=34), and the reduced form was shown to be increased in this group (n=16) for the first time. Reduced HMGB1 was chemotactic for peripheral blood leukocytes, and sputum HMGB1 correlated with sputum total cell counts. HMGB1, but not RAGE, expression was ~3-fold higher ex vivo in ASM of severe asthmatics (n=16). ASM and human bronchial epithelial cells (HBECs) expressed both HMGB1 and cell-surface RAGE in vitro. HMGB1 expression was upregulated in ASM cells stimulated with inflammatory cytokines. HMGB1 stimulation caused increased reactive oxygen species production in ASM cells from non-asthmatics, but not in asthmatics; ASM contraction and inhibition of ASM cell migration and HBEC wound healing. These results suggest that HMGB1 promotes inflammatory cell recruitment, impairs epithelial and ASM repair, and promotes ASM contraction in asthma. Further work is required to determine whether antagonising HMGB1 or its receptors would be a viable therapeutic approach for the treatment of asthma.
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Léguillette, Renaud. "Expression of smooth muscle myosin heavy chain isoforms in asthma and their molecular mechanics." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103169.
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Two smooth muscle (SM) myosin heavy chain isoforms, generated by alternative mRNA splicing, differ by the presence (SM-B) or absence (SM-A) of a 7 amino acid insert in the motor domain. The rate of actin filament propulsion (nu max) of SM-B, as measured in the in vitro motility assay, is 2-fold greater than that of SM-A. I investigated the expression and function of these isoforms in healthy SM and in asthma. First, I determined the sequence of the SM-B isoform in human SM and quantified its expression at the mRNA and protein levels in several human organs. The SM-B isoform was mostly expressed in rapidly contracting phasic SM. I then purified myosin from multiple rat organs and found a rank correlation between SM-B content and numax.I then quantified the expression of SM-B and several other contractile protein genes in endobronchial biopsies from normal and asthmatic subjects. SM-B, myosin light chain kinase (MLCK), which is responsible for myosin activation, and transgelin, a ubiquitously expressed actin binding protein but whose function is unknown, were overexpressed in the asthmatic biopsies. The increased SM-B expression and myosin activation, due to the increased MLCK expression, both contribute to the increased rate of shortening of the asthmatic airway SM. In addition, I showed that beyond its enzymatic effects, MLCK mechanically enhances numax. The binding of SM22 to actin, however, did not alter numax.
Finally, I addressed the mechanisms behind the unique capacity of SM to maintain force at low energy cost, namely the latch-state. This property is mostly observed in SM-A containing, tonic muscle. Using a laser trap, I measured the binding force of unphosphorylated (non-active) SM-A and SM-B myosin isoforms and found that they can both attach to actin and maintain force. I also measured numax at different MgADP concentrations and found that SM-A has a greater affinity for MgADP. Because MgADP must be released before myosin can detach from actin, these results suggest that the SMA isoform remains attached longer to actin, allowing it to get into the latch-state. These findings explain the greater propensity of tonic muscle to get into the latch-state.
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Naseer, Tanveer 1971. "In vivo expression of interleukin-12 and interleukin-13 in the pathogenesis of asthma." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23925.
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IL-12 and IL-13 are recently discovered cytokines which belong to Th1 and Th2 subtypes, respectively. To further support the hypothesis that Th2-type cytokines are involved in asthma, mRNA levels for IL-12 and IL-13 were measured in bronchial biopsies from asthmatics and normal controls as well as in moderately severe asthmatics before and after corticosteroid therapy using the technique of in situ hybridization. The number of IL-13 mRNA positive cells in asthmatics was significantly higher than that found in normal controls. However, there was a significant decrease in the number of IL-12 mRNA positive cells in asthmatic biopsies compared to normal controls. Following corticosteroid therapy, a significant decrease in IL-13 mRNA positive cells and an increase in the number of cells expressing IL-12 mRNA was detected. The results suggest an in vivo role of the cytokines in modulating allergic responses and support the role of Th2 type cytokines in asthma.
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Wicks, James. "The expression and regulation of ADAM33, a novel asthma susceptibility gene, during myofibrolast differentiation." Thesis, University of Southampton, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432038.
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Farahani, Mosavar. "Regulation of histamine Hâ†1-receptor coupling and expression in cultured human airway smooth muscle cells." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263099.
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Scott, Mark George Hunter. "Control of cyclic AMP-mediated and ß₂ adrenergic receptor gene expression in cultured human airway smooth muscle cells." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324123.
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Josephs, Lynn K. "A longitudinal study of bronchial responsiveness and its relationship to the clinical expression of asthma." Thesis, University of Southampton, 1992. https://eprints.soton.ac.uk/370379/.
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Carney, Katharine W. "Expression patterns and functional roles of amphiregulin in murine CD4+ T cells." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669191.
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Florsheim, Esther Borges. "Mecanismos envolvidos na indução da inflamação alérgica pulmonar pela serino protease subtilisina." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-12122014-161448/.
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A asma ocupacional é a forma mais comum de doença pulmonar relacionada ao trabalho e vários dos casos reportados estão correlacionados à exposição de proteases. A serino protease subtilisina foi bastante utilizada na década de 60 e foi a principal responsável pela alta incidência de asma na indústria de detergente. Este projeto visou a desenvolver um modelo murino de inflamação alérgica pulmonar à subtilisina e caracterizar os mecanismos principais envolvidos nessa resposta. A sensibilização e desafio com subtilisina induziu doença alérgica pulmonar, verificada pela eosinofilia às vias aéreas, produção de muco, IgE total, hiper reatividade brônquica e produção de citocinas tipo II no pulmão. Estas respostas foram dependentes da atividade enzimática da subtilisina, PAR-2, receptor de IL-33 ST2, IL-1R e da sinalização via MyD88. Em conjunto, nossos resultados estabelecem um novo modelo experimental de asma ocupacional induzida por subtilisina e fornece os principais mecanismos moleculares responsáveis pela inflamação alérgica.Occupational asthma is the most common form of pulmonary disease related to work. Most of occupational asthma cases reported are strictly correlated with proteases exposure. Serine protease subtilisin was widely used in the detergent industry during the 60s, which resulted in increased incidence of occupational asthma. We aimed to develop and characterize a murine model of occupational asthma using subtilisin as allergen. Briefly, sensitization and challenge with subtilisin triggered lung allergic inflammation, as accessed by eosinophilic influx to the airways, mucus production, and increased levels of type II cytokines. Subtilisin induced total IgE and airway hyperactivity. Allergic responses to subtilisin were dependent on its serine protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, IL-1R, and Myd88 signaling. Together, these data establish a new murine model of occupational asthma induced by subtilisin and provide the main molecular mechanisms responsible for allergic inflammation.
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Sundaram, Kruthika. "Expression And Function Of Human IkappaBzeta In Lung Inflammation." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436224271.
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Redington, Anthony Edward. "Fibrogenic mediators in atopic asthma : expression of endothelin, transforming growth factor-beta and basic fibroblast growth factor." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242665.
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Erickson, Nancy Ann [Verfasser]. "Expression Analyses of CLCA Members in the Feline Respiratory Tract – Biomolecules in Feline Asthma? / Nancy Ann Erickson." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1240230397/34.
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Joubert, Philippe. "Expression and function of chemokine receptors on airway smooth muscle cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103385.
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Asthma is a respiratory disease that affects 2.5-3 million Canadians. This condition is characterized by a Th2-driven immune response that implicates the infiltration of eosinophils and remodelling of the airways. In the last decade, airway smooth muscle cells (ASMC) have became the subject of intense research in the field of inflammatory lung diseases including asthma. It is known that ASMC respond to a wide variety of inflammatory mediators such as cytokines and chemokines. Function of ASMC in the context of asthma has extended beyond its traditional role of a structural cell. Indeed, it is believed that they can participate in the initiation and the perpetuation of the inflammatory response that takes place in the airway of asthmatic subjects. The general aim of this work was to investigate the role of ASMC in the pathogenesis of asthma. More specifically, we studied the expression of two C-C chemokine receptors, CCR3 and CCR1 in the context of asthma.For the first time, this work describes the expression of chemokine receptors by ASMC. We have shown that eotaxin, an important chemokine in asthma, induces migration of ASMC through the activation of CCR3. Although CCR3 expression is not regulated by Th2 cytokines in vitro, ASMC isolated from asthmatic patients expressed intrinsically higher levels of the surface receptor when compared to controls. We also describe the expression of CCR1 by ASMC, a receptor involved in airway remodelling in an animal model of asthma. We reported the expression of CCR1 mRNA in biopsies obtained from mild, moderate and severe asthmatics and showed that mild group express the highest level of CCR1. We also confirmed that ASMC express the receptor in vivo and showed that stimulation of this receptor with its ligands induces intra-cellular calcium mobilization, which confirms its functionality. Regulation of CCR1 on ASMC was also assessed using proinflammatory, Th1 and Th2 cytokines. We found that TNF-alpha and to a lesser extent, IFN-gamma, upregulated CCR1 mRNA and protein expression, while Th2 cytokines had no effect. The effect of these two cytokines was totally suppressed by either dexamethasone or mithramycin.
Collectively, our results demonstrate the expression of functional C-C chemokine receptors by ASMC. Interestingly, we have shown that CCR3 activation mediates ASMC migration and provides a new possible mechanism for the increased smooth muscle mass observed in asthmatic patients. Although the exact function of the CCR1 expressed by ASMC is unknown, our results suggest an involvement in asthma pathogenesis, possibly through airway remodelling.
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Carvalho, Liliana Sofia Machado de. "Expression of cyclooxygenase enzymes and prostaglandin E2 receptors in inflammatory airway diseases." Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/6347.
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Dissertação para obtenção do Grau de Mestre
em Genética Molecular e BiomedicinaAspirin-intolerant asthma (AIA) is a syndrome where the interplay between cyclooxygenase (COX) and lipoxygenase (LOX) pathways is evident and is characterized by several abnormalities in the regulation and biosynthesis of eicosanoid mediators and eicosanoid receptors. Several observations indicate the presence of a complex change in the arachidonic acid (AA) metabolism in patients who suffer from AIA. However, previous studies showed some discrepant results when upper and lower airways were analyzed, and there are no clear explanations for this. The inflammatory responses in upper airways are often associated with the presence of nasal polyps, structures never seen in the lower airways. In this study, upper and lower airways were compared, in order to verify if the multiple factors of the COX pathway are differentially regulated considering both respiratory tracts. To perform the experiments, fibroblasts from nasal mucosa (NM) and bronchial mucosa (BM) of non-asthmatic subjects undergoing corrective surgery and fibrobronchoscopy, respectively, (control group) were compared with NM, nasal polyp (NP), and BM fibroblasts isolated from non-asthmatic and AIA patients suffering from chronic rhinosinusitis (CRS) with NP. The data presented in this investigation suggest that in lower airways, the presence of aspirin intolerance does not seem to alter the expression of COX enzymes or the production of prostaglandin (PG) E2. Considering the expression of the EP receptors, the data suggest significant differences through fibroblasts from upper airways tissues. The differences observed between upper and lower airways combined with others verified in previous studies might contribute to the pathogenesis of nasal polyposis.
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Byström, Jonas. "Eosinophil Cationic Protein : Expression Levels and Polymorphisms." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2059.
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The eosinophil cationic protein (ECP) is usually associated with the eosinophil granulocyte. In this thesis the presence and production of this protein has been studied in two other cells. The circulating monocyte was found to contain ECP mRNA and small amounts of ECP, one thousand times less than that found in the eosinophil. The production decreased by differentiation of the myelomonoblastic cell line U937 into a macrophage phenotype. Submucosal lung macrophages did not stain for ECP and alveolar macrophages did not contain ECP mRNA. The circulating neutrophil contains ECP at a level hundred fold less than the eosinophil. We found that the protein is located to the primary granules of the neutrophil but could detect no ECP mRNA in the cell. It was shown in vitro that the protein was taken up by the cell and partly transported to the primary granules. The uptake did not seem to be receptor mediated. Upon stimulation of the neutrophils, ECP previously taken up, was re-secreted.
The ECP protein is heterogeneous both to molecular characteristics and to function. To evaluate if a genetic component is involved, the ECP gene was analysed in 70 individuals. Three single nucleotide polymorphisms (SNP´s) were found, denoted 277(C>T), 434(G>C) and 562(G>C). The two first were located to the mature peptide-coding region and would change the amino acids, arg45cys and arg97thr. The prevalence of the most common SNP, 434, was evaluated in two eosinophil-related diseases, allergy/asthma and Hodgkin Lymphoma (HL). Forty-three HL patients were evaluated and it was found that the 434GG was significantly more prevalent in patients having nodular sclerosis (NS) as compared to other histologies (p=0.03). Erythrocyte sedimentation rate was also related to the 434GG genotype (p=0.009). In 209 medical students 434GG was more common (p=0.002) in those who indicated allergy. The genotype was unrelated to the production of IgE antibodies to allergens. In analysis of 76 subjects with asthma it was found that the 434GG genotype was significantly more common among allergic asthmatics (p=0.04). Asthma and HL-NS are characterized by fibrosis and eosinophils and ECP has been suggested in fibrosis development.
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Hadaway, Matthew. "Effect of induced airway inflammation in asthma : the expression of trefoil factors, secretoglobins and genes involved in histone acetylation." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/62168/1/Matthew_Hadaway_Thesis.pdf.
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Asthma is an incapacitating disease of the respiratory system, which causes extensive morbidity and mortality worldwide. Asthma affects more than 300 million people globally(Masoli et al. 2004). In Australia, it affects 10.2% of the population (Masoli et al. 2004) and causes 60,000 people to be hospitalised annually. Health care expenditure due to asthma in Australia was $606 million in 2004–2005. There are four primary biological factors that function in the initiation and exacerbation of asthma. Airway inflammation is important as it is often the first response to an airway insult, initiating the three other components: bronchoconstriction, mucus hyper-secretion and hyper-reactivity. The mediators involved in asthma are still not well understood, and current anti-inflammatory corticosteroid treatments are not effective with all asthmatics. As there is currently no cure for asthma, and airway inflammation is the primary component of the disease, it is important that we understand and investigate the mediators of airway inflammation to look for a potential cure and to produce better therapeutics to treat the inflammation.
Trefoil factors (TFFs) and secretoglobins (SCGBs) are small secreted proteins involved in the mediation of inflammation and epithelial restitution. TFFs are pro-inflammatory and SCGBs anti-inflammatory by nature. The hypothesis of this study is that in response to induced acute airway inflammation, the expression of TFF1 and TFF3 will increase and expression of SCGB1A1 and SCGB3A2 will decrease in non-asthmatics (N-A), asthmatics medicating with bronchodilators (A-BD) and asthmatics medicating with corticosteroids (A-ST). When comparing the three groups, we expect to see higher expression of the TFFs in the A-BD group compared to the N-A and A-ST groups, indicating that inflammation is mediated by TFFs in asthma and that corticosteroid medication controls their expression as part of the control of inflammation. We expect to see the opposite with SCGBs, with a greater decrease in the A-BD group compared to the other two groups, suggesting that the A-BD group has the least anti-inflammatory activity in response to inflammatory insult.
Epigenetic modification plays a role in the regulation of genes that initiate disease states such as inflammatory conditions and cancers. Histone acetylation is one such modification, which involves the acetylation of histones in chromatin by histone acetyltransferases (HATs). This increases the transcription of genes involved with inflammation or enrols histone deacetylases (HDACs) to down-regulate the transcription of inflammatory genes. These HATs and HDACs work in a homeostatic fashion; however, in the event of inflammation, increased HAT activity can stimulate further inflammation, which is believed to be the mechanism involved in some inflammatory diseases. This study hypothesises that in response to inflammation, the expression of HDACs (HDAC1-5) will decrease and the expression of HATs (NCOA1-3, HAT-1 and CREBBP) will increase in all groups. When comparing the expression between the groups, it was expected that a greater decrease in HDACs and a greater increase in HATs will be seen in the A-BD group compared to the other two groups. This would identify histone acetylation as a mechanism involved in the inflammatory condition of asthma and indicate that corticosteroids may treat the inflammation in asthma at least in part by controlling histone acetylation.
The aim of the project was to compare the expression of inflammatory genes TFF1, TFF3, SCGB1A1 and SCGB3A2, as well as to compare the gene expression of HDAC1-5, NCOA1-3, HAT-1 and CREBBP within and between N-A (n=15), A-BD (n=15) and A-ST (n=15) groups in response to inflammation. This was performed by collecting airway cells and proteins by sputum induction in three sessions. The sessions were coordinated into an initial baseline collection (SI-1), followed by a second session at least one week later (SI-2) and a third session, six hours after SI-2 to collect a sample containing the resultant acute inflammation caused in SI-2 (SI-3). Analysis of the SI-1 and SI-2 samples in all three groups had high amounts of variability between samples. The samples were taken at least one weak apart and the environmental stimuli on each participant outside of the testing sessions could not be controlled. For this reason, the SI-1 samples were not used for analysis; instead SI-2 and SI-3 samples were compared as they were same-day collections, reducing the probability of differences being due to anything other than the sputum induction.
The gene expressions of the TFFs, SCGBs, HDACs and HATs were analysed using real-time PCR. Western blot analysis was performed to analyse the protein concentrations of the TFFs and SCGBs in secreted fractions of the sputum collection. Both the secreted and intracellular protein fractions collected from the sputum inductions for pre- and post-inflammation (SI-2, SI-3) samples of the N-A and A-BD groups were analysed using a proteomic method called iTRAQ. This allowed the comparison of the change in protein expression as a result of airway inflammation in each group. This technique was used as a discovery method to identify novel proteins that are modulated by induced acute airway inflammation. Any proteins of interest would then be further validated and used for future research.
Inflammation was achieved in the SI-3 samples of the N-A group with a 21% unit increase in % neutrophils compared to SI-2 (p=0.01). The N-A group had a marked 5.5-fold decrease in HDAC1 gene expression in SI-3 compared to SI-2 (p=0.03). No differences were seen in any of the TFFs, SCGBs or any of the rest of the HDACs and HATs. Western blot data did not display any significant changes in the protein levels of the TFFs and SCGBs analysed. However, non-significant analysis of the data displayed increases in TFF1 and TFF3, and decreases in SCGB1A1 and SCGB3A2 for the majority of SI-3 samples compared to SI-2.
The A-BD group also presented a marked increase in neutrophils in the SI-3 samples compared to SI-2 (27% unit increase, p=0.04). The A-BD group had a significant increase in TFF3 and SCGB1A1 gene expression concomitant with induced acute airway inflammation. A 7.3-fold increase in TFF3 (p=0.05) in SI-3 indicated that TFF3 is linked to inflammation in asthmatics. A 2.8-fold increase in SCGB1A1 (p=0.03) indicated that this gene is also up-regulated, suggesting that this SCGB is expressed to try to combat induced acute airway inflammation. No significant changes were seen in any of the other genes analysed. Western blot data did not display any significant changes in the protein levels of the TFFs and SCGBs analysed. However, non-significant analysis of the data displayed an increase in TFF1 and TFF3, and a decrease in SCGB1A1 and SCGB3A2 in SI-3, similar to that seen in the N-A group.
The A-ST group was different from the A-BD group, characterised by the use of inhaled corticosteroid medication to treat asthma symptoms. Inhaled corticosteroids are known to treat asthma symptoms through the control of inflammation. Therefore, it was expected that corticosteroid medication would also control the expression of TFFs, SCGBs, HATs and HDACs. Gene expression results only identified a 7.6-fold decrease in HDAC2 expression in SI-3 (p=0.001), which is proposed to be due to the up-regulation of HDAC2 protein that is known to be a function of corticosteroid use. Western blot data did not display any significant changes in the protein levels of the TFFs and SCGBs analysed.
The gene expression in SI-2 and SI-3 in each group was compared. When comparing the A-BD group to the N-A group, a 9-fold increase in TFF3 (p=0.008) and a 34-fold increase in SCGB1A1 (p=0.03) were seen in the SI-3 samples. Comparisons of the A-ST group to the N-A group had an increased expression in SI-2 samples for HDAC5 (3.6-fold, p=0.04), NCOA2 (8.5-fold, p=0.04), NCOA3 (17-fold, p=0.01), HAT-1 (36-fold, p=0.003) and CREBBP (13-fold, p=0.001). The SI-3 samples in the A-ST group compared to the N-A group had increased expression for HDAC1 (6.4-fold, p=0.04), HDAC5 (5.2-fold, p=0.008), NCOA2 (9.6-fold, p=0.03), NCOA3 (16-fold, p=0.06), HAT-1 (41-fold, p<0.001) and CREBBP (31-fold, p=0.001). Comparisons of the A-ST group to the A-BD group had SI-2 increases in HDAC1 (3.8-fold, p=0.03), NCOA3 (4.5-fold, p=0.03), HAT-1 (5.3-fold, p=0.01) and CREBBP (23-fold, p=0.001), while SI-3 comparisons saw a decrease in HDAC2 (41-fold, p=0.008) and increases in HAT-1 (4.3-fold, p=0.003) and CREBBP (40-fold, p=0.001). Results showed that TFF3 and SCGB1A1 expression is higher in asthmatics than non-asthmatics and that histone acetylation is more active in the A-ST group than either the N-A or A-BD group, which suggests that histone acetylation activity may be positively correlated with asthma severity.
The iTRAQ proteomic analysis of the secreted protein samples identified the SCGB1A1 protein and found it to be decreased in both the N-A and A-BD groups post-inflammation, but significantly so only in the A-BD group. Although no significant results were obtained from the western blot data, both groups displayed a decrease in SCGB1A1 concentration in SI-3 samples, suggesting a correlation with the proteomic data. Only 31 peptides were identified from the secreted samples. The intracellular iTRAQ analysis successfully identified 664 peptides, eight of which had differential expression in association with induced acute airway inflammation. Significant increases were seen in the A-BD group in SI-3 compared to SI-2 than in the N-A group in chloride intracellular channel protein 1, keratin-19, eosinophil cationic protein, calnexin, peroxiredoxin-5, and ATP-synthase delta subunit, while decreases were seen in cystatin-A and mucin-5AC. The iTRAQ analysis was only a discovery measure and further validation must be performed.
In summary, the expression of TFFs and SCGBs differed between non-asthmatics and asthmatics. It is clear that TFF3 is active in the airway inflammation associated with asthma as indicated by an increase associated with inflammation in the A-BD group compared to the N-A group. Results for HDAC and HAT genes showed high HAT expression in the A-ST group compared to the N-A and A-BD groups, suggesting that histone acetyltransferases may be responsible for the characteristic unregulated inflammatory symptoms of asthmatics taking corticosteroids. Interestingly, corticosteroid medication did not seem to silence the expression of the analysed HAT genes, which indicates that corticosteroids may not control inflammation by direct regulation of HATs, but instead by competition, most probably with HDAC2 protein. As a discovery tool, iTRAQ is a potent method to both identify and compare the concentration of proteins between samples. The method is a powerful first step into the identification of novel proteins that are regulated in response to different treatments.
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Karagiannidis, Christian. "Activin A und TGF-[beta]1 [TGF-Beta-1] bei Asthma bronchiale: differentielle Expression und gemeinsame Funktionen sowie deren Regulation durch Glukokortikoide." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974673056.
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Haitchi, Hans Michael. "The expression and function of the asthma susceptibility gene, a Disintegrin and Metalloprotease (ADAM) 33, in airways of normal and asthmatic subjects and in developing lungs." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/380396/.
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Asthma affects 1 in 12 adults and 1 in 10 children in the UK. It is a complex disease involving genetic and environmental factors. ADAM33 is an asthma susceptibility gene whose polymorphic variation has been linked to asthma and bronchial hyperresponsiveness, as well as decline in lung function in asthma and COPD and reduced lung function in young children. ADAM33 mRNA is almost exclusively expressed in mesenchymal cells, such as fibroblasts, myofibroblasts and smooth muscle cells. These cells play an important role in modelling of the airways during lung development and in remodelling of the airway in established disease. As the function of ADAM33 and its role in asthma is not known, this thesis tested the hypotheses that: ADAM33 is differentially expressed in normal and asthmatic lungs; and ADAM33 is involved in embryonic/fetal lung development where the influence of an allergic maternal environment affects ADAM33 to contribute to the development of asthma. To test the hypothesis that ADAM33 is differentially expressed in asthma, bronchial biopsies and brushings from adult subjects were examined. Using RT-qPCR all previously described splice variants were detected in the biopsies. No disease specific difference for any of the mRNA splice variants could be detected. Using immunohistochemistry, it was shown, for the first time that ADAM33 is found mainly in the bronchial smooth muscle, consistent with its genetic association with BHR. Computer-aided image analysis of ADAM33 expression did not reveal a disease-specific difference, consistent with the mRNA data. No expression of ADAM33 could be demonstrated in bronchial brushings containing more than 95% epithelial cells. To test the hypothesis that ADAM33 is involved in embryonic lung development human embryonic lung (HEL) and mouse tissues were examined. Using RT-qPCR, the same splice variants were detected in HEL as in adult bronchial tissue, however Western blot analysis revealed an extra ADAM33 protein band in HELs compared to adult lungs suggesting a different role of ADAM33 in developing lung. Expression of ADAM33 increased in HELs from 7 to 9 weeks post conception and a similar increase occurred when HELs were cultured in a newly developed HEL explant culture system suggesting that this is a useful model for studying human lung development. ADAM33 could be successfully knocked down using siRNA in the mesenchymal progenitor cells grown in culture from HELs paving the way for knock-down in whole HEL tissue. When ADAM33 mRNA expression was studied during murine lung development it was detectable from as early as embryonic day 11 and two significant increments in expression could be seen. The first occurred during the pseudoglandular stage when spontaneous peristaltic contractions occur and the second one after birth when the lungs inflate at the beginning of air breathing, suggesting that mechanical forces might induce ADAM33. To test the hypothesis that ADAM33 and asthma are influenced by maternal allergy, a mouse model using bronchial hyperresponsiveness susceptible mice (A/J mice) was used. Maternal allergy was induced using ovalbumin and the offspring were studied for ADAM33 expression and lung function. Maternal allergy had a suppressive effect on ADAM33 mRNA directly after birth which was similar to the findings in HEL cultured for 18 days in the presence of IL-13. Maternal allergy also induced increased BHR to methacholine in 4 weeks old offspring. Although no direct causal relationship with ADAM33 was established, these findings suggest a potential gene-environment interaction. In conclusion this thesis provides novel data regarding the expression and localisation of ADAM33 in embryonic and adult lung. It also suggests a potential role for ADAM33 in lung development and highlights the effect that maternal allergy has on airway reactivity of offspring that carry the ADAM33 susceptibility gene, consistent with a role for ADAM33 in the early-life origins of asthma.
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Berenchtein, Beatriz. "A INFLUÊNCIA DO STRESS NA EXPRESSÃO CLÍNICA DA ASMA INFANTIL." Universidade Metodista de São Paulo, 2004. http://tede.metodista.br/jspui/handle/tede/1449.
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Previous issue date: 2004-11-22Asthma is the most frequent chronic disease in childhood and stress is considered one of the triggering and aggravating agents of bronchospasm in this patients. The aim of this work was investigate the influence of stress in the clinical expression of asthma and your association with the asthma attacks in children. The asthmatic children answered to a stress scale (LIPP E LUCARELLI, 1998) and their parents answered some questions about the frequency of symptoms and asthma attacks, sleep disturbance, school absenteeism, physical exercises limitations, frequency of use of medicines, their behavior during their child asthma attacks, the triggering agents of crises, their socio-economic status and education level. The results showed that the asthmatic children were more stressed than those from the control group, specially the children with severe asthma. Also, stress can intensify frequency of asthma attacks, physical exercises limitations, school absences and sleep disturbance. The children that had been diagnosed for a long period were less stressed. The results from this study suggest that stress can precipitate or exacerbate asthma attacks. That shows necessity of more researches to refine the knowledge about this subject.
A asma é a doença crônica mais freqüente na infância e o stress é considerado um dos agentes desencadeantes e agravantes do broncoespasmo nesses pacientes. O objetivo deste trabalho foi investigar a influência do stress na expressão clínica da asma e sua associação com as crises em crianças. Para verificar a presença de stress, utilizou-se a Escala de Stress Infantil (LIPP E LUCARELLI, 1998) e por meio de um questionário aplicado aos pais, observou-se freqüência de sintomas e crises de asma, as alterações do sono, o absenteísmo escolar, as limitações à prática de atividade física, a freqüência de uso de broncodilatador, as condutas dos pais durante as crises de asma, os fatores associados ao desencadeamento das crises, o poder aquisitivo e o grau de instrução do chefe da família. Observou-se que as crianças com asma estavam mais estressadas que as crianças do grupo controle, principalmente aquelas com maior gravidade da doença. Os resultados indicam que a presença de stress pode intensificar a freqüência de sintomas da asma, a limitação à atividade física, o absenteísmo escolar e as interrupções do sono. O maior tempo de diagnóstico de asma implicou em menor ocorrência de stress, sugerindo a existência de um fator de adaptação à doença. Conclui-se que o stress é um fator importante no desencadeamento e agravamento das crises de asma nas crianças e observa-se a necessidade de maiores pesquisas na aérea para aprofundar os conhecimentos sobre esse assunto.
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Bradley, Jennifer L. "Obesity and Asthma: Adiponectin Receptor 1 (Adipo R1) and Adiponectin Receptor 2 (Adipo R2) are expressed by normal human bronchial epithelial (NHBE) cells at air-liquid interface (ALI) and expression changes with IL-13 stimulation." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4576.
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Obesity is recognized as an important risk factor for the development of many chronic diseases such as hypertension, Type 2 diabetes mellitus (T2DM) cardiovascular disease, cancer, renal disease, neurologic dysfunction, metabolic syndrome and asthma (3, 4). Circulating serum adiponectin levels in obese asthmatics have been reported to be low. Therefore, we aimed to investigate the role of adiponectin in a mucus hypersecretion model and hypothesized that adiponectin would decrease IL-13 induced MUC5AC expression from differentiated NHBE cells and that increasing concentrations of IL-13 would cause a decrease in Adipo R1 and Adipo R2 expression. MUC5AC expression with exposure to adiponectin was not significant. However, mRNA expression of Adipo R1 and Adipo R2 was significantly decreased by stimulation of IL-13 for acute (24 hours) and chronic (14 days) exposure. Therefore, the obese state and specifically IL-13 concentration could play a role in Adipo R1 and Adipo R2 expression within NHBE cells.
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Hartley, Judith Ann. "Developing methods for the identification and isolation of dendritic cells from peripheral blood and their application to the study of high affinity IgE receptor (Fc#epsilon#RI) expression by dendritic cells in health and atopic asthma." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285820.
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Vorsprach, Monique [Verfasser], Marino [Gutachter] Venerito, and Marek [Gutachter] Lommatzsch. "Expression von Cyclooxygenasen (COX-1 und COX-2) und Lipoxygenase (5-LOX) in Nasenpolypen und Bronchialschleimhaut bei Patienten mit Asthma bronchiale, rezidivierender Polyposis nasi und Analgetikainteroleranz : Korrelation mit klinischen und funktionellen Parametern / Monique Vorsprach ; Gutachter: Marino Venerito, Marek Lommatzsch." Magdeburg : Universitätsbibliothek Otto-von-Guericke-Universität, 2020. http://d-nb.info/1220035637/34.
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Pasanen, A. (Anu). "Genetic susceptibility to childhood bronchiolitis." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526218991.
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Abstract Bronchiolitis is an infection of the small airways of the lung and is a common reason for infant hospitalizations. The most common causative pathogen is the respiratory syncytial virus (RSV). Genetic factors are thought to influence the risk of bronchiolitis, and better knowledge of bronchiolitis genetics will likely help to elucidate the disease process. Severe bronchiolitis in childhood may predispose to asthma. Therefore, an effective treatment of bronchiolitis may affect the present-day as well as lifelong respiratory health. In this project, we aimed to identify genetic loci of bronchiolitis susceptibility by a genome-wide association study (GWAS) and suitable follow-up studies, and to study a previously asthma-associated CDHR3 variant for association across five bronchiolitis populations by meta-analysis. We performed the GWAS on a Finnish-Swedish case-control population and identified several loci below the suggestive genome-wide significance level. Of these, three variants showed nominal associations in a replication population from the Netherlands. One of the loci affected KCND3 expression, and two others were intergenic variants with putative regulatory potential. In a follow-up study conducted on a GWAS sub population, we identified the NKG2D locus as a candidate of susceptibility to bronchiolitis. The genomic region encompassing NKG2D variants was reportedly associated with NKG2D mRNA and protein abundance. We validated the association between NKG2D genotypes and protein expression with flow cytometry. The association between NKG2D and bronchiolitis was supported by a Finnish replication study. The meta-analysis was performed on populations from Denmark, Finland, Sweden, Germany, and the Netherlands. A potential virus-specific role for the CDHR3 variant was detected in a population that comprised mostly RSV-negative cases. In conclusion, we identified new candidates of bronchiolitis susceptibility in GWAS and subsequent studies. We found the CDHR3 variant was a potential susceptibility factor in severe non-RSV bronchiolitis and asthma. Our preliminary results provide interesting starting points for further studies. In the future, better understanding of the disease mechanisms and the relationship of bronchiolitis and asthma could provide means to design new therapeutic optionsTiivistelmä Bronkioliitti on viruksen aiheuttama alahengitystieinfektio, joka usein johtaa pienten lasten sairaalahoitoon. Yleisin bronkioliitin aiheuttaja lapsilla on respiratory syncytial -virus (RSV). Perintötekijöiden arvellaan altistavan bronkioliitille, joten uusi tieto altistavista geeneistä voi auttaa ymmärtämään taudin taustalla olevia biologisia mekanismeja. Lapsuusiän bronkioliitin ajatellaan voivan altistaa astmalle, joten bronkioliitin tehokas hoito voi vaikuttaa merkittävästi hengitysterveyteen myös pitkällä aikavälillä. Työssä pyrittiin selvittämään lapsuusajan bronkioliitille altistavia geneettisiä tekijöitä genominlaajuisella assosiaatiokartoituksella, joka toteutettiin suomalais-ruotsalaisessa tapaus-verrokkiväestössä. Löydökset pyrittiin varmentamaan soveltuvilla jatkotutkimuksilla. Lisäksi tarkastelimme astmalle altistavaa CDHR3-geenin polymorfismia viidessä eurooppalaisessa bronkioliittikohortissa käyttäen meta-analyysia. Assosiaatiokartoituksessa havaittiin useita mahdollisia bronkioliittialttiuteen vaikuttavia geenikohtia. Näistä kolme sai tukea hollantilaisessa väestössä tehdyssä assosiaatioanalyysissä, jossa testattiin assosiaatiokartoituksen lupaavimmat löydökset. Yksi altistavista polymorfismeista vaikutti KCND3-geenin ilmentymiseen, ja kaksi muuta olivat geenien välisiä, mahdollisesti geeninsäätelyyn osallistuvia variantteja. Assosiaatiokartoituksen osa-analyysissä NKG2D tunnistettiin mahdolliseksi bronkioliitille altistavaksi geeniksi. NKG2D-immuunireseptorin alentunut ilmentyminen voi tulostemme perusteella altistaa vakavalle bronkioliitille. Meta-analyysissä, jonka tutkimuskohortit olivat peräisin Tanskasta, Suomesta, Ruotsista, Saksasta ja Hollannista, todettiin mahdollinen yhteys CDHR3-geenin polymorfismin ja muun viruksen kuin RSV:n aiheuttaman bronkioliitin välillä. Toteutimme tässä työssä ensimmäisen genominlaajuisen bronkioliittialttiutta koskevan assosiaatiokartoituksen. Assosiaatiokartoituksessa, sitä seuranneissa jatkotutkimuksissa ja meta-analyysissä tunnistimme useita lupaavia alttiusgeenejä, mutta tuloksemme vaativat varmentamista suuremmissa tutkimusväestöissä
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Cheng, Fang-Yi, and 鄭芳怡. "Feasibility Study of TSLPR /IL-7Rα Expression for Children with Allergic Asthma." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/zsy3j7.
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Lee, Tsai-Chun, and 李采純. "The Correlation Between Thymic Stromal Lymphopoietin Receptor Complex Expression and Pediatric Asthma." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/wsc85p.
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碩士國立虎尾科技大學
生物科技研究所
101
Recent studies found that cytokine thymic stromal lymphopoietin (TSLP) play a very important role and related with allergic inflammatory diseases including atopic dermatitis, rhinitis, and asthma. The TSLP receptor (TSLPR) is a heterodimeric cytokine receptor consisting of the IL-7 receptor alpha chain (IL-7Rα) and a TSLP-specific receptor chain. In our research, our specific aim is focused on the relationship between thymic stromal lymphopoietin receptor complex expression and the severity pediatric asthma. TSLPR chain can express on dendritic cells, T cells, B cells, mast cells, natural killer (NK) cells, eosinophil cells and monocytes. IL-7Rα chain can express on bone marrow lymphoid precursors, pro-B cells, NK cells, naïve and memory CD4+ and CD8+ T cells, dendritic cells, monocytes/macrophages, mast cells and eosinophil cells. T cells, monocytes, dendritic cells, NK cells, mast cells and eosinophil cells can coexpress the TSLPR chain and IL-7Rα chain. In some report, they found that genetic polymorphisms will affect the expression of the TSLPR chain and IL-7Rα chain. The SNP of TSLPR chain is one possible factor correlated with the susceptibility to atopic asthmatic disease. Also, polymorphisms of IL-7Rα chain are associated with allergic asthma susceptibility. One report found that TSLPR expressing cells have potential to modulate expression of the TSLPR when exist in a milieu of proallergic and proinflammatory cytokines and other factors (e.g., allergens, bacterial products, and lipid mediators). This result indicates acquired environmental factors can also affect the expression of the TSLPR. Until now, it is unclear that if the expression of TSLPR complex is correlated with genetic factors or environmental factors or both. In recent study, we found that TSLPR chain and IL-7Rα chain mRNA expression in PBMC layer of the AA (atopic, asthmatic) group children is more significantly higher than NN (non-atopic, non-asthmatic) group children. In another study of Hung et al., stimulation of human THP-1 cell by Der p2 did not affect the expression of TSLPR chain and IL-7Rα chain. The TSLP receptor expression mechanism in other cell types is still need further investigation. We hope that the expression of TSLPR can be applied to the evaluation of the severity of asthma and to be as a disease marker in the future.
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"Activation of NF-[kappa]B and p38 MAPK regulating the expression of cytokines, chemokines and adhesion molecules upon the co-culture of human eosinophils and bronchial epithelial cells." Thesis, 2005. http://library.cuhk.edu.hk/record=b6074068.
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Co-culture of eosinophils and BEAS-2B cells was found to increase the release of cytokine IL-6 and chemokines MIG, MCP-1, IL-8 and IP-10 and up-regulate the corresponding genes expression in BEAS-2B cells or eosinophils. Interaction of eosinophil-BEAS-2B cells could also elevate adhesion molecules ICAM-1, VCAM-1, ICAM-3, and CD49d expression on the surface of BEAS-2B cells, and CD18 and ICAM-3 on eosinophils, and up-regulate ICAM-1 gene expression in BEAS-2B cells. Lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha could induce or further induce ICAM-1 expression on eosinophils and BEAS-2B cells upon their interaction. Moreover, activities of both NF-kappaB and p38 MAPK in BEAS-2B cells were markedly elevated after co-cultured with eosinophils.Freshly isolated eosinophils from human peripheral blood and confluent BEAS-2B cells were co-cultured together in tissue culture plate for a pre-determined time period. Cytokines including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma and chemokines regulated upon activation normal T cell expressed and secreted (RANTES), monokine induced by interferon-gamma (MIG), monocyte chemoattractant protein (MCP)-1, IL-8, and interferon inducible protein (IP)-10 in culture supernatant were evaluated by protein array and quantified by cytometric bead array (CBA) kit of Th1/Th2 cytokines, inflammatory cytokines, and human chemokines using flow cytometry and enzyme linked immunosorbent assay (ELISA) kit.
In order to investigate the immunopathological mechanism in allergic asthma of eosinophils interacting with bronchial epithelium in inflammation site, a in vitro system of co-culture of human bronchial epithelial cells and eosinophils was set up to mimic the inflammatory reaction.
In summary, co-culture of epithelial cells, BEAS-2B cells, and eosinophils could activate NF-kappaB and p38 MAPK signal transduction pathways to induce inflammatory cytokine IL-6, and chemokines IL-8, MCP-1, MIG and IP-10 release in culture supernatant, and up-regulated the expression of surface adhesion molecules ICAM-1, VCAM-1, ICAM-3 and CD49d protein on BEAS-2B, and CD18 and ICAM-3 on eosinophils. (Abstract shortened by UMI.)
In this study, co-culture of a human epithelial cell line, BEAS-2B cells, and peripheral eosinophils was adopted as an in vitro model to investigate the effect of interaction of epithelial cells and eosinophils in airways on pathophysiology of asthma.
Wang Chengbin.
"July 2005."
Advisers: Wai kei Lam; Chun kwok Wong; Yaping Tian.
Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3723.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (p. 119-134).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract in English and Chinese.
School code: 1307.
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Movassagh, Hesamaldin. "Expression of Semaphorin 3E in Asthma and its role in Allergic Airway Disease." 2016. http://hdl.handle.net/1993/31121.
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Asthma is a chronic condition characterized by variable airflow obstruction, bronchial hyper-responsiveness, airway inflammation and remodeling. In spite of tremendous advances, the regulatory mechanisms controlling these pathological features have not yet been completely addressed. From an immunological perspective, type 2 inflammation and eosinophilic infiltration are the most striking hallmarks of asthma. At physiological level, structural changes such as increase in smooth muscle mass take the center stage which is usually associated with clinical measures of asthma. There might be some regulatory mediators capable of tuning airway inflammation and remodeling under homeostatic conditions but abrogated in asthmatic conditions.
Semaphorin 3E (Sema3E) is an axon guidance molecule that is ubiquitously expressed and plays diverse roles in structural and inflammatory cells such as regulation of cell migration, proliferation and angiogenesis. However, its role in clinical and experimental asthma remains unclear. In this thesis, I have set out to uncover the expression and function of Sema3E in allergic asthma. It is generally hypothesized that Sema3E is down-regulated in allergic asthma which orchestrates the function of inflammatory (dendritic cells and neutrophils) and structural (airway smooth muscle) cells. Replenishment of Sema3E, which is suppressed under asthmatic conditions, could confer protection against allergic asthma by modulation of cellular functions.
I began by comparing the expression of Sema3E between allergic asthmatics and healthy subjects. A remarkable down-regulation of Sema3E under asthmatic patients was observed which was further confirmed in a mouse model of the disease. Decreased expression of Sema3E was specifically demonstrated on bronchial epithelial cells obtained from asthmatic patients at both mRNA and protein levels.
To address the function of Sema3E in allergic asthma in vivo, I extended my studies to mouse models of the disease and demonstrated that Sema3e gene deletion results in exacerbated allergic asthma pathology induced by allergen exposure. To investigate the translational relevance of my findings, I performed treatment of an asthmatic mouse model with exogenous Sema3E in which its intranasal administration attenuated airway inflammation, remodeling and hyper-responsiveness. The mechanism underlying Sema3E’s role in pathogenesis of allergic asthma was extensively studied indicating a crucial role of this mediator in modulation of dendritic cells and neutrophils functions. Our data demonstrated that both dendritic cells and neutrophils express the Sema3E high affinity receptor, PlexinD1, which makes them responsive to Sema3E treatment. Then, I studied expression and function of PlexinD1 on human airway smooth muscle (ASM) cells. I found that PlexinD1 surface expression was reduced on ASM cells from asthmatic patients. Treatment of ASM cells with Sema3E inhibited their proliferation and migration as the characteristic feature of airway remodeling. Suppression of Rac1 GTPase activity and phosphorylation of Akt/PI3K and ERK/MAPK were found as signaling mechanisms underlying Sema3E’s inhibitory effects. Together, these findings show that Sema3E thereby appears as a novel regulatory mediator, upstream of pro-allergic events, suggestive of a new approach to attenuate allergic asthma deficits.May 2016
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Wu, Wen-Chia, and 吳文嘉. "Relationship between Sialyl Glycan Expression on T Cells and Endophenotypes of Childhood Asthma." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/94597722629521297350.
Full textAbstract:
碩士國立臺灣大學
流行病學與預防醫學研究所
104
Background: Asthma is a common chronic inflammatory disease in children. Helper T (Th) cells and regulatory T cells (Tregs) play important role of the pathogenesis of asthma and lead to various endophenotypes. The expression level of functional adhesion molecules, sialyl Lewis x (CD15s) and sialyl 6-sulfo Lewis x (G152) glycan, on memory Th cells are associated with the severity of allergic diseases. The association between the expression level of sialyl glycans and asthma endophenotypes remain unclear and needs further investigation. Methods: Thirty-one asthma patients and nineteen healthy controls aged 6 to 15 were recruited from NTUCH and a clinic in 2015 and 2016. The percentage of glycan-expressing cells among memory Th cells was detected by flow cytometry. The association between the expression of sialyl glycan and several asthma endophenotypes, such as severity, blood eosinophils and serum total IgE level, was investigated. Results: CD15s and G152 glycans on memory Th cells are upregulated in asthma patients compared with healthy controls. The population of suppressive CD15s+ Tregs among CD4+ T cells was significantly lower in the moderate to severe group of asthma. Blood eosinophils and serum total IgE and, as two indicators of the exacerbation of asthma were associated with G152 glycan and G159 glycan respectively. Conclusions:CD15s and G152 glycans were associated with the current status of childhood asthma. Patients expressing the higher level of G152 glycan and less G159 glycan on central helper memory T cells would have higher risk on exacerbation.
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Chia-Hsiu and 許家修. "Selective Cysteinyl Leukotriene Receptor Antagonist Modulates Matrix Metalloproteinase Expression in a Mouse Asthma Model." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/74042283014051297734.
Full textAbstract:
碩士中山醫學大學
醫學研究所
96
Atopic disease including allergic rhinitis and asthma is common in the world and Taiwan. The disease is generally considered to be caused by interaction of genetic and environmental factors. The incidence of asthma has increased substantially in the last two decades. New medication is developed rapidly in recent years to apply to allergic asthma, since lots of people have investigated about these. However, now existing drugs just offer partial relief of symptoms in such disease. Therefore, the aim of our study was to investigate the complicated mechanism of asthma by different drugs. The more effective drugs to suppress asthmatic airway response are expectantly to be developed. Even we can then reverse the damaged lung tissue after airway remodeling. As we known today, asthma is a repeated chronic inflammatory disease. It is characterized by a complex response of pulmonary eosinophilia, edema, mucus hypersecretion, and airway hyperreactivity. Under the condition of long-term asthma, airway remodeling may develop by goblet cells increased, subepithelial fibrosis, airway smooth muscle mass increased and vascular hyperplasia. These make asthma control more difficult. Many mechanisms, mediators and cytokines, including cysteinyl leukotrienes (CysLTs), are related to these structural changes. To determine the effect of a specific CysLT receptor antagonist on airway inflammation and remodeling, a mouse asthma model was applied. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, were given intranasal OVA on Day 14 and Days 25-27. Randomized treatment groups of sensitized mice were fed a CysLT receptor antagonist singulair (montelukast, MK-476), verlukast (MK-679) or placebo from Days 15-27. Prednisolone is one kind of steroid which is known as efficient anti-inflammatory agent. It is used extensively at clinic for long time. One group of sensitized mice in the study would be fed with prednisolone according to the same feeding protocol as other study groups. The steroid-treated group will act as standard index of treatment efficacy. On Day 28, pulmonary mechanics were determined noninvasively using whole body plethysmography. The mice were then sacrificed; the serum, the bronchoalveolar lavage fluid (BALF) and the lung tissue were obtained for further evaluation of airway inflammation and remodeling. In present study, the OVA-sensitized mice developed a significant airway inflammatory response than control group. The serum IgE level, the percentage of BALF eosinophils, the airway collagen deposition and peribronchial fibrosis were significantly elevated in OVA-sensitized group (P < 0.001 vs. control group). The significant airway inflammatory response in OVA-sensitized mice was inhibited by prednisolone or montelukast (P < 0.01 vs. sensitized group). MK-679, given during airway remodeling, reduced airway inflammation less effectively (P < 0.05 vs. sensitized group) but reversed structural changes more effectively (P < 0.001 vs. sensitized group) than prednisolone. Montelukast also reversed the airway structural changes to significant level as MK-679 (P < 0.001 vs. sensitized group). Here the study also showed that BALF matrix metalloproteinase (MMP)-2 and MMP-9 levels were proportional to the extent of airway remodeling. Airway hyperresponsiveness to methacholine was observed in OVA-sensitized mice (P < 0.01 vs. control group). Airway hyperresponsiveness could be reversed by prednisolone, montelukast and MK-679. However, when the OVA-sensitized mice were challenged with higher dose of methacholine (20mg/ml), only the prednisolone and montelukast reversed airway hyperresponsiveness to significant level (P < 0.05 vs. sensitized group). In conclusion, this study demonstrates that many cytokines participate in airway inflammation and remodeling. The CysLT plays a more important role than other cytokines in chronic allergic airway inflammation. Thus the selective CysLT receptor antagonist inhibits airway remodeling more effectively than prednisolone. Furthermore, the MMP-2 and MMP-9 may be useful for monitoring airway remodeling.
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Yasruel, Zivart. "Expression of membrane-anchored and soluble isoforms of interleukin-5 receptor Ü mRNA in bronchial asthma." Thesis, 1996. http://spectrum.library.concordia.ca/6253/1/MM18457.pdf.
Full text
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Revez, Joana Nunes Mexia Allen 1989. "A new variant in the interleukin-6 receptor (IL-6R) gene increases gene expression and asthma risk." Master's thesis, 2013. http://hdl.handle.net/10451/9449.
Full textAbstract:
Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências, 2013A interleucina-6 (IL-6) é uma citocina envolvida na asma alérgica, que atua nas suas células-alvo através de um recetor constituído por pelo menos duas subunidades membranares: uma glicoproteína de associação ao ligando (IL-6R) e uma glicoproteína transdutora de sinal (gp130). Embora a gp130 se expresse na grande maioria das células, apenas algumas são diretamente estimuladas pela IL-6, porque a expressão da IL-6R membranar (mIL-6R) é limitada a hepatócitos e determinadas células imunes. No entanto, a IL-6R também existe sob forma solúvel (sIL-6R), que tanto pode ser formada por clivagem da mIL-6R, como por splicing alternativo. Uma vez ligada à IL-6, a sIL-6R pode associar-se à gp130, estimulando as células por uma via alternativa, também viável em células que não expressam mIL-6R. A variante rs2228145, no gene IL6R, encontra-se na região que codifica para o local de corte da mIL-6R e é considerada o principal determinante genético dos níveis de sIL-6R, representando cerca de 19% da sua variabilidade. Portadores do alelo de risco têm elevados níveis de sIL-6R e maior risco de asma. No entanto, a percentagem de variação nos níveis de sIL-6R explicada geneticamente é estimada em 70%, muito superior aos 19% supramencionados, pelo que é possível que outras variantes no IL6R, ou próximo deste, também contribuam para a sua variabilidade independentemente da rs2228145, e possivelmente afetem o risco de asma. Para testar esta hipótese, neste estudo (1) efetuámos uma imputação exaustiva de variantes comuns na região do IL6R; (2) testámos a associação entre as variantes obtidas e os níveis de sIL-6R de 360 indivíduos; (3) replicámos o estudo numa amostra independente de 354 indivíduos para as variantes que apresentaram associação mais forte; e (4) testámos a associação das variantes replicadas (a) com os níveis de transcrito do IL6R (em dois estudos independentes; N = 851 e N = 5 191) e (b) com o risco de asma (N = 47 514). Segue-se uma descrição mais pormenorizada de todos estes pontos. Numa primeira fase, medimos em duplicado as concentrações serológicas de sIL-6R de 360 asmáticos já genotipados. Após eliminar variabilidades técnicas, calculámos a média dos níveis corrigidos de sIL-6R para cada indivíduo e normalizámos a distribuição global das medições. Não se verificaram efeitos significativos do sexo ou da idade. Tendo o 1000 Genomes Project como referência, imputámos 452 variantes no IL6R (± 50 kb) dos 360 asmáticos, e testámos a sua associação com os níveis de sIL-6R, bem como a de outras 19 variantes diretamente genotipadas nestes indivíduos. A variante que apresentou maior grau de associação (P = 0.0005) com os níveis de sIL-6R ajustados pelo rs4129267, uma variante correlacionada (r2 = 0.99) com a rs2228145, foi a rs12083537, e a associação manteve-se significativa (P = 0.0496) após correção pelo número de variantes testadas. Três variantes independentes demonstraram estar significativamente associadas com os níveis de sIL-6R ajustados pelas variantes rs4129267 e rs12083537, mas qualquer destas associações deixou de ser significativa depois de corrigir pelo número de variantes testadas. Para confirmar a associação entre a variante rs12083537 e os níveis de sIL-6R, replicámos o estudo de associação em 354 indivíduos não relacionados com os anteriores. Após ajustamento pelos efeitos do rs4129267, detetámos uma associação significativa entre o rs12083537 e os níveis de sIL-6R (P = 0.033), sendo a direção do efeito a mesma que a da análise prévia. Estes resultados confirmam portanto que rs12083537, ou uma variante correlacionada com esta, regula os níveis serológicos de sIL-6R. Depois de combinar as duas amostras onde se efetuaram os estudos de associação (N = 714), o rs12083537 passou a explicar 2.2% da variabilidade dos níveis de sIL-6R ajustados pelo rs4129267 (P = 6x10-5), sendo que antes do ajuste explicava 0.15%. O alelo rs12083537:G reduziu os níveis de sIL-6R de forma semelhante nas três classes genotípicas do rs4129267. Para ajudar a compreender o mecanismo molecular pelo qual o rs12083537 afeta os níveis de sIL-6R, estudámos em seguida os níveis de RNA mensageiro (mRNA) do IL6R num grupo de gémeos adolescentes (N = 851) para determinar se esta variante influenciava os níveis da transcrição. Não foi detetada associação significativa entre o rs12083537 e os níveis de mRNA, quer com uma sonda para a região 3’UTR, quer com uma sonda para o exão 9. Por outro lado, detetámos uma associação significativa entre a variante rs4129267 e os níveis de transcrito do IL6R. Contraintuitivamente, o alelo rs4129267:T, que aumenta os níveis de sIL- 6R, demonstrou associação com baixos níveis de transcrito do IL6R. Para garantir que a ausência de associação entre o rs12083537 e os níveis de mRNA do IL6R não se deveu a baixo poder de deteção da nossa amostra, realizámos uma análise semelhante à anterior num estudo independente e maior (N = 5 191). Neste estudo, após correção pelo número de sondas testadas, não foi detetada uma associação significativa entre a variante e os níveis de mRNA do IL6R. A sonda para a qual a associação foi mais forte é complementar à região 3’UTR (P = 0.0031); o alelo rs12083537:A que aumenta os níveis de sIL-6R esteve associado com uma redução dos níveis de transcrito do IL6R. Por fim, como o alelo rs2228145:C aumenta não só os níveis de sIL-6R mas também o risco de asma, testámos a hipótese de o rs12083537 também ser um fator genético de risco para a asma. A associação entre esta variante e asma foi testada em 47 514 indivíduos de três estudos independentes, dos quais 16 705 eram asmáticos diagnosticados por um médico. O alelo rs12083537:A foi detetado com mais frequência em asmáticos do que nao-asmáticos nos três estudos individuais, sendo a associação global entre o rs12083537 e o risco de asma fraca mas estatisticamente significativa (OR = 1.039, 95% I.C. = 1.002 – 1.078, P = 0.0419). A variante rs12083537 localizada no intrão 1 do IL6R, a 2.9 kb do exão 1, revelou estar significativamente associada com os níveis de sIL-6R independentemente da variante rs4129267, e a associação foi confirmada quando replicámos a análise. A variante localiza-se numa região do gene que, em pelo menos quatro linhas celulares, incluindo fibroblastos pulmonares e queratinócitos, tem elevado grau de metilação (H3K4Me1). Este tipo de modificação de histonas está associada a enhancers e promotores, sendo portanto plausível que o rs12083537 influencie a transcrição do IL6R. No entanto, não foi detetada associação significativa entre o rs12083537 e os níveis de mRNA do IL6R, pelo que o mecanismo de ação da variante permanece por elucidar. Também verificámos que o alelo rs4129267:T, que aumenta os níveis de sIL-6R, está associado a baixos níveis de mRNA do IL6R. As medições para as quais se verificou esta associação foram feitas com uma sonda que se liga ao exão 9, o qual pode ser removido por splicing alternativo. Assim, as medições em causa correspondem apenas aos níveis de mRNA que não sofreu splicing. Tendo em conta que o alelo rs4129267:T está associado a um aumento do splicing do exão 9, é portanto de esperar que os níveis da isoforma que não sofreu splicing diminuam na presença deste alelo. Por fim, verificámos que a variante rs12083537 está significativamente associada com o risco de asma. Com base na nossa análise, cada alelo rs12083537:A aumenta os níveis serológicos de sIL-6R cerca de 2.4 vezes e o risco de asma1.04 vezes. Em conclusão, este estudo demonstra que pelo menos duas variantes genéticas influenciam os níveis serológicos de sIL-6R. Como tal, estudos de resposta clínica ao tocilizumab, um anticorpo monoclonal para o IL-6R já aprovado para o tratamento da artrite reumatoide, devem avaliar a contribuição das diversas variantes que regulam os níveis de sIL-6R. Pontuações de risco genético cumulativo poderão ser úteis para explicar variabilidade na respostas clínica ao tocilizumab.
O principal determinante genético dos níveis de IL-6R solúvel é a variante rs2228145, que se encontra no local de corte da proteína IL-6R. Por cada alelo Ala, os níveis de sIL-6R aumentam por ~20 ng/ml e o risco de asma aumenta 1.09 vezes. No entanto, esta variante não explica a totalidade da componente hereditária dos níveis de sIL-6R. É portanto possível que outras variantes no gene IL6R também contribuam para variações nos níveis de sIL-6R e influenciem o risco de asma. Para testar esta hipótese, imputámos 471 variantes comuns no IL6R e testámos a sua associação com os níveis serológicos de sIL-6R em 360 indivíduos. Uma variante intrónica (rs12083537) apresentou associação com os níveis de sIL-6R independentemente da variante rs4129267 (P = 0.0005). Observámos uma associação significativa e consistente ao replicar o estudo em 354 indivíduos (P = 0.033). Cada cópia do alelo rs12083537:A aumentou os níveis de sIL-6R em 2.4 ng/ml. Na análise dos níveis de mRNA em dois estudos independentes não foram identificadas associações significativas entre a variante rs12083537 e os níveis de transcrição do IL6R. Por outro lado, o alelo rs12083537:A aumentou o risco de asma 1.04 vezes (P = 0.0419) na análise de 16 705 asmáticos e 30 908 controlos. Pontuações de risco genético poderão portanto ser úteis para explicar variabilidade na resposta clínica ao tocilizumab, um anticorpo monoclonal contra o IL-6R.
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Chagani, Tabassum. "Apoptosis and expression of Fas (CD95) and Fas ligand (CD95L) in the airways of severe asthma subjects." Thesis, 2001. http://hdl.handle.net/2429/11659.
Full textAbstract:
Airway epithelial denudation is characteristic of asthma and may contribute to non-specific
bronchial hyperresponsiveness and airway remodeling. Apoptotic pathway in these cells is
mediated by Fas-FasL interaction. Loss of the protective immune function by FasL could
permit prolonged survival of inflammatory cells in the airway mucosa. We postulated that 1)
the process of epithelial apoptosis is enhanced in asthma, 2) there is decreased epithelial
expression of FasL which may contribute to the persistence of inflammatory cells in the
airway walls of asthma subjects. We performed the TUNEL assay to detect the extent of
apoptosis, and immunohistochemical staining to determine the expression of Fas and FasL in
asthmatic airways. Formalin fixed paraffin embedded airway sections from 17 severe asthma
subjects, 16 chronic asthma subjects and 18 control subjects were studied. Images of the
conducting airways were captured using a Spot Cooled digital camera linked to a computer.
Quantification for TUNEL and immunohistochemical staining was performed using Image
Pro-Plus® software. Epithelial apoptosis was increased in the severe asthma versus chronic
asthma and control groups (p = 0.0004 all airways; p = 0.01 cartilaginous airways; p = 0.004
membranous airways). Epithelial expression of Fas and FasL was increased in the severe
asthma group compared to chronic asthma and control groups (p = 0.04 and 0.0004
respectively for all airways combined). There was no difference in epithelial Fas expression
between the groups when cartilaginous and membranous airways were analyzed separately.
Epithelial FasL expression was increased in the severe asthma group in both the cartilaginous
and membranous airways compared to chronic asthma and control groups (p = 0.0004 and
0.0008 respectively). Fas expressing inflammatory cells in the wall of membranous airways
were increased in the severe asthma versus chronic asthma and control groups. There was no
statistically significant difference between the study groups in FasL expressing inflammatory
cells in the airway wall compartments. We demonstrate that there is increased apoptosis and
epithelial expression of Fas and FasL in the airways of severe asthma group. Alteration in
Fas or FasL expression does not contribute to persistence of asthma inflammation but could
contribute to epithelial apoptosis.
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Jin, C., CP Shelburne, G. Li, EN Potts, KJ Riebe, GD Sempowski, WM Foster, and SN Abraham. "Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation." Thesis, 2011. http://hdl.handle.net/10161/2358.
Full textAbstract:
Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft–enriched, CD63(+) endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.Dissertation
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Wang, Chien-Neng, and 王建能. "Study on Shikonin and Brazilin Inhibited Mitogens Induced Th2 Cytokines Expression in Vitro and Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/20408005427422609396.
Full textAbstract:
碩士中國醫藥大學
基礎醫學研究所
98
Asthma patients has dramatically increased during the past decade years. Medicines for asthma such as inhaled corticosteroid, anti-histamine or anti-leukotriene, can rescue the late phase symptom but reappear without taking. Inhalation of corticosteroid showed side effects. Therefore, it needs to develop the drug of asthma. Shikonin and brazilin are two components of Chinese herbal medicines, isolated from Lithospermum erythrorhizon and Caesalpinia sappatin L. Shikonin has been reported to treat macular eruption, measles, sore-throat and burns and brazilin has been used to treat chronic intestinal inflammation, amenorrhea and Enterorrhagia. We choose shikonin and brazilin to investigate the therapeutic effects on allergic asthma in vitro and in vivo. EL4 T cell treated with different doses of shikonin（0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3μM）and brazilin（0.1 μM, 0.3 μM, 1 μM, 10 μM, 30 μM）combined with PMA and cAMP to induce T helper 2 (TH2) cytokines release. We analyzed T helper 2 (TH2) cytokines by ELISA and transcription factors mRNA expression by real-time PCR. We also investigated the therapeutic effects of shikonin and brazilin in a murine asthma model. We found that different doses of shikonin and brazilin have no cytotoxicity by trypan-blue exclusion and could dose-dependently reduce TH2 cytokines (IL-4, IL-5) expression and GATA-3 and c-Maf expression. We also found that shikonin and brazilin could inhibit TH2-specific transcription factors mRNA but not TH1 transcription factor (T-bet) mRNA. Shikonin and brazilin inhibited antigen–induced bronchial alveolar fluid (BALF) IL-4, IL-5 and eotaxin expression, reduced eosinophils cells infiltration in BALF and lungs, and airway hyperresoseiveness(AHR). Our study suggested that shikonin can effectively suppressed TH2 cytokines release in vitro and inhibited allergic inflammation and airway hyperresponsiveness in a murine model of asthma. Key words: shikonin, brazilin, type II T helper cell, allergic asthma.