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H2S as a novel biomarker and therapeutic target for asthma

dc.contributor.advisorWang, Rui
dc.contributor.authorWang, Peipei
dc.date.accessioned2016-02-08T19:54:48Z
dc.date.available2016-02-08T19:54:48Z
dc.date.created2015
dc.date.issued2015
dc.identifier.urihttp://knowledgecommons.lakeheadu.ca/handle/2453/731
dc.description.abstractAsthma is a chronic inflammatory disease with hyper-responsive bronchoconstriction and airway remodeling, leading to extensive airway narrowing. The pathophysiology of asthma remains unclear. The literature shows that the cystathionine gamma lysase (CSE)/ hydrogen sulfide (H2S) system participates in the regulation of airway contractility and immune response. In this PhD thesis study we found that CSE was a major enzyme responsible for endogenous H2S synthesis in the lung and spleen. CSE gene knock-out (CSE-KO) dramatically decreased H2S production rates in these two organs. In an asthma model established via ovalbumin (OVA)-sensitization and challenge, airway resistance of CSE-KO mice (12-16 weeks old), in response to aerosolized methacholine (MCh) at 12.5 mg/ml, was two times higher than that of wild type (WT) mice (12-16 weeks old). CSE-KO mice also developed more peribronchial inflammation and had higher levels of type-2 helper T cell (TH2) cytokines in bronchoalveolar lavage fluid (BALF). As allergic asthma is more prevalent among children than in adults, we next used young (3-4 weeks old) and old (7-8 months old) mice to observe whether the CSE/H2S system was involved in early onset asthma. With the same intensity and duration of OVA-treatments, young WT mice developed much more severe asthma with greater lung resistance, higher levels of eosinophils and TH2 cytokines in BALF, and more peribronchial inflammation than did old WT mice. This age-dependent propensity for immunoreaction and asthma development resulted from lower levels of CSE expression and H2S production in splenocytes from young mice, which was reversed by H2S supplementation. Human umbilical cord blood mononuclear cells also had lower level of CSE proteins than peripheral blood mononuclear cell from human adults. CSE-KO mice had more severe asthma than WT mice but without age-dependent variation. Lower endogenous levels of CSE/H2S promoted the differentiation of splenocytes into type-2 cytokine-generating cells in young WT mice and in CSE-KO mice at all ages. This effect was suppressed by H2S supplementation. CSE/H2S-induced inhibition of type-2 immunity was not mediated by STAT-6 activation. Instead, H2S caused S-sulfhydration of GATA3 in splenocytes and decreased GATA3 nuclear translocation, leading to the inhibition of type-2 immunity. We also found that CSE expression in the airways of WT mice increased in an age-dependent manner. In the absence of allergen exposure, lower abundance of CSE in young WT mice or absence of CSE in young/old CSE-KO mice aggravated airway responsiveness to MCh challenge by more than twice compared to old WT mice. In conclusion, CSE/H2S in peripheral lymph tissues and the lung suppresses allergen-induced type-2 immunity, airway responsiveness and the consequential asthma. Lower activity of the CSE/H2S pathway renders a higher incidence of allergic asthma in childhood.en_US
dc.language.isoen_USen_US
dc.subjectAsthma researchen_US
dc.subjectHydrogen sulphide (H2S)en_US
dc.titleH2S as a novel biomarker and therapeutic target for asthmaen_US
dc.typeDissertation
etd.degree.nameDoctor of Philosophy
etd.degree.levelDoctoral
etd.degree.disciplineBiotechnology
etd.degree.grantorLakehead University
dc.contributor.committeememberYang, Guangdong
dc.contributor.committeememberKhaper, Neelam


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