Role of airway epithelial glutaminase in asthma

University Of Virginia Charlottesville, Charlottesville VA

Investigators

Linked publications & trials

Abstract

Description (provided by applicant): Infection with human RV is one of the most common causes of worsening asthma symptoms. The mechanism by which this common upper respiratory pathogen causes severe expiratory flow limitation remains unclear. Recent observations from our laboratory may provide insight. Specifically, we have shown that: 1) breath condensate pH is low during asthma exacerbations and increases with corticosteroid treatment; 2) this fall in pH may lead to several aspects of asthma pathophysiology, including inflammatory cell necrosis and nitrogen oxide toxification; 3) low breath condensate pH in asthma is associated with low breath condensate ammonium concentrations; 4) human airway epithelial cells produce ammonium from glutamine stoichiometrically and express the enzyme, glutaminase; 5) human airway epithelial glutaminase is inhibited by IFN and upregulated by corticosteroids; and 6) human RV infections cause a decrease in breath condensate pH and ammonium levels. These observations suggest that RV infections may inhibit airway epithelial glutaminase by Th-1 cytokine-mediated and corticosteroid-inhibitable mechanisms, preventing normal buffering of protons and allowing airway acidification to lead to downstream pathophysiologic features of an acute asthma exacerbation. In this project, we will define the relevance of this proposed pathway to the pathogenesis of exacerbations of human asthma by testing the following three hypothesis: (1) airway acidification contributes to the pathophysiology of acute asthma; (2) airway acid is buffered by ammonia, a product of epithelial glutaminase; and (3) RV infection decreases airway epithelial glutaminase activity. In testing these hypotheses, we will make extensive use of resources unique to the asthma center and provide critical assays and materials to other components of the center. We anticipate that this project will provide insight into the mechanism by which RV infection leads to exacerbations of human asthma, and will define several potential targets for therapeutic intervention.