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

Abstract

ObjectiveThe phenomena manifested during inflammation require interplay between circulating effector cells, local resident cells, soluble mediators and genetic host factors to establish, develop and maintain itself. Of the molecues involed in the initiation and perpetuation of acute allergic inflammation in asthma, 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 and Methods and TreatmentTo 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.ResultsIn 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).

Heterogeneity in Human Embryonic Stem Cells May Prevent Endodermal Guided Differentiation

“…In contrast, culture in a commercially available BEGM (with tri-iodothyronin and retinoic acid but without BSA) promoted differentiation to predominantly bronchiolar alveolar cell (i.e., Clara cell) phenotype. Lung lineage-specific cell differentiation was achieved in a relatively shorter span of time (22 days) in contrast to other reported lung lineage culture conditions [22][23][24][25][26][27][28][29][30]. These culture media, normally used to maintain and grow mature cells, could successfully induce differentiation of pluripotent embryonic stem cells into three types of mature lung lineage-specific non-ciliated cells.…”

“…Previous work [22][23][24][25][26][27][28][29][30] has demonstrated differentiation steps to AEII cells from murine ES cells and the hES H7 cell line.…”

Effects of prior oral exposure to combinations of environmental immunosuppressive agents on ovalbumin allergen-induced allergic airway inflammation in Balb/c mice

“…These syndromes may result in the activation of mast cell degranulation and aggravation of asthma-like symptoms such as labored respiration, increase airway resistance and wheezing 29 . In addition, the aggravation of allergic airway inflammation is in line with our preliminary study, which found that combined exposure to certain environmental chemicals can suppress acquired immune responses 12 .…”

P21-activated kinase in inflammatory and cardiovascular disease

“…In addition, recent expert opinions further support the idea for PAK1 involvement in these disorders and that PAK1 is a suitable target for pharmacological inhibition [148]. Moreover, a robust amount of literature indicates that NADPH oxidase is heavily implicated in the development of allergic reactions [149–152]. In spite of this initial evidence, it is still unclear in which specific allergic disorders PAK1 is involved, and what could be the role of PAK1 in regulating NADPH oxidase under these conditions.…”