The phospholipase A2s (PLA2)s are a group of enzymes that catalyze the rate-limiting step in the formation of eicosanoids such as leukotrienes (LT)s and prostaglandins (PG)s. This application for sustained support focuses on secreted phospholipase A2 group X (sPLA2-X) in the pathophysiology of asthma. During the prior funding cycle, we addressed the novel hypothesis that the airway epithelium serves as a regulator of eicosanoid production through the expression of sPLA2s. A total of 10 mammalian sPLA2s have been described. From our research, sPLA2-X emerged as the dominant sPLA2 expressed in the airways. The amount of sPLA2-X protein is increased in the airway lining fluid of patients with asthma, and is strongly expressed in the airway epithelium. Further, we found that sPLA2-X initiates LT synthesis in target cells including eosinophils and mast cells implicated in asthma. Murine models indicate that sPLA2-X is necessary for the development of ovalbumin-induced airway inflammation and airway hyperresponsiveness (AHR). We provide new data that sPLA2-X is necessary for the development of house dust mite induced airway inflammation as well as macrophage polarization. In this application we strive to further elucidate the mechanism by which sPLA2-X initiates airway inflammation and mediates bronchoconstriction in asthma. Our primary hypothesis is that epithelial-derived sPLA2-X is necessary for the development of allergen- induced airway inflammation and serves as an initiator of bronchoconstriction in inflamed airways. A corollary hypothesis is that sPLA2-X plays a crucial role in the adaptive immune response to inhaled allergen through macrophage polarization.
In Specific Aim 1 we focus on the specific role of epithelial- derived sPLA2-X during the development of allergen-induced airway immunopathology, and examine the function of epithelial sPLA2-X during the sensitization versus effector phases. Using primary human epithelial cells, we examine the regulation of secretion and activation of sPLA2-X.
In Specific Aim 2, we examine the role of sPLA2-X in macrophage polarization towards a M2 phenotype, and the precise role of the sPLA2-X macrophage axis in the adaptive immune response to allergen.
In Specific Aim 3, we conduct a translational study on the role of sPLA2-X during hyperpnea-induced bronchoconstriction using a novel pharmacological inhibitor of sPLA2-X in a guinea pig model. These studies will provide important insights into the mechanism of allergen-induced airway dysfunction mediated by the epithelium and a strong basis for the further development of a new approach to treating asthma through the selective inhibition of sPLA2-X.
During the last funding cycle, secreted phospholipase A2 group X (sPLA2-X) emerged as a potential regulator of airway pathophysiology in asthma. The present application seeks to examine the importance of epithelial expression of this enzyme, the cellular mechanism leading to the development of airway inflammation, and the specific role of the enzyme in airway hyperresponsiveness. This important information is likely to lead to a novel therapeutic approach for asthma.
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