Defining the molecular role of gp91phox in the immune manifestation of acute allergic asthma using a preclinical murine model

To clarify the role of gp91phox subunit of NADPH oxidase in the development and progression of an acute allergic asthma phenotype, we induced allergen dependent inflammation in a gp91phox-/- single knockout and a gp91phox-/-MMP-12-/- double knockout mouse models.In the knockout mice, both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicate a regulatory role for NADPH oxidase in development of allergic asthma. While T cell mediated functions like Th2 cytokine secretion, and proliferation to OVA were upregulated synchronous with the overall robustness of the asthma phenotype, macrophage upregulation in functions such as proliferation, and mixed lymphocyte reaction indicate a regulatory role for gp91phox and an overall non-involvement or synergistic involvement of MMP12 in the response pathway (comparing data from gp91phox-/- and gp91phox-/-MMP-12-/- mice).Asthma is a complex syndrome with well described pathology. However, animal and clinical studies in humans continue to provide conflicting data on contribution of local cells viz. airway epithelial, endothelial and smooth muscle cells, fibroblasts etc vs. cells recruited from circulation. Asthma is characterized by accumulation of inflammatory cells in the lung and airways, secretion of predominantly Th2 cytokines in the lung and airways, epithelial desquamation, goblet cell hyperplasia, mucus hypersecretion and thickening of submucosa resulting in bronchoconstriction and airway hyperresponsiveness. Dysregulated immunity seems to suppress Th1 response and triggers Th2 response whose development is promoted by antigen presenting cells. Th2 cytokines (IL-4, 5, 9, 13) from these cells of which IL-4 and 13 promote