Viral infections are a common cause of asthma exacerbations in children and adults. It is proposed that viral respiratory infections increase airway inflammation through the generation of cytokines including IL-8, and the subsequent recruitment of neutrophils to the airway. Considerable evidence supports the importance of integrin-mediated adhesion for neutrophil recruitment in response to inflammatory stimuli. It is our hypothesis that virus-generated inflammatory events in the airway and integrin-ligand interactions coordinately regulate neutrophil polarization and migration by modulating intracellular signaling pathways via the p38 MAPK pathway. Using live imaging approaches and analysis of intracellular signaling pathways, we propose to dissect how integrin-mediated adhesion and viral-induced changes in chemoattractants modulate neutrophil function and how these effects may be differentially regulated in neutrophils isolated from patients with asthma. Accordingly, the specific aims for the current application are to: (1) examine how integrin-mediated adhesion to fibronectin and IL-8 coordinately regulate signaling via p38 MAPK, oxidative burst activity and migration of neutrophils and determine if neutrophils isolated from the peripheral blood of asthmatics are differentially regulated; (2) test the hypothesis that p38 MAPK is required for the integrin-mediated regulation of neutrophil adhesion, polarization and migration in response to viral infection; (3) identify mechanisms by which p38 MAPK regulates neutrophil polarization and migration in response to viral infection and the role of the Rho family of GTPases in this process. The long-term goal of our research is to characterize how viral infection modulates neutrophil function and how these effects may contribute to the pathogenesis of viral-induced asthma exacerbation.
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