NADPH Oxidase Has a Regulatory Role in Acute Allergic Asthma

Objective: For the establishment of inflammation, a constant interplay between different effector cells from circulation, local resident cells, soluble mediators and genetic host factors is required. Molecular mechanisms, initiating and perpetuating inflammation, in particular, the involvement of effector cells in redox reactions for producing O2- (superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them. Materials, Methods and Treatment: To clarify the role of NADPH oxidase in T cell-initiated, macrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- mouse. Results: 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, indicates 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 up-regulated synchronous with the overall robustness of the asthma phenotype, macrophage up-regulation in functions such as proliferation, mixed lymphocyte reaction, and MCP-1 directed chemotaxis, but downregulation of respiratory burst response indicates a forking in their signaling pathways. gp91phox-/- MMP12 double knockout (DKO) mice show a similar phenotype as the gp91phox-/- showing the non-involvement or synergistic involvement of MMP12 in the response pathway. In mixed lymphocyte reaction using the Increased B7.1 but reduced B7.2 and MHC class II expression indicating alteration of co-stimulatory molecule expression critical for T cell activation on both gp91phox-/- and DKO mice may explain the mechanism by which gp91phox may regulate Th2 pathway in allergic asthma