The airway epithelium plays a key role in host defense, clearance of inhaled particles and maintenance of alveolar integrity. Additionally, the bronchial epithelial cells modulate airway inflammation by inducing synthesis and secretion of pro- inflammatory cytokines such as interleukin-8 (IL-8), a major chemotactic and activation factor for polymorphonuclear neutrophils in the airway. In a number of inflammatory lung diseases, enhanced IL-8 secretion is associated with morbidity and mortality. Lysophosphatidic acid (LPA), a potent naturally occurring bioactive phospholipid metabolite has been implicated in regulating a wide range of cellular responses such as proliferation, cytoskeletal rearrangement and metastasis. Human bronchial epithelial cells (HBEpCs), express endothelial differentiation gene (Edg) receptors, which are heterotrimeric G- protein coupled, bind to LPA with high affinity and transduce signals via activation of protein kinases and phospholipases. Although some critical cellular functions regulated by LPA have been recognized, little is known regarding the role of LPA as an inflammatory mediator. Preliminary studies suggest that LPA is a potent stimulator of IL-8 secretion in HBEpCs leading to the hypothesis: LPA is a regulator of airway inflammation by mediating IL-8 synthesis and secretion in HBEpCs. To test this hypothesis, the following specific aims will investigate the mechanisms of LPA-mediated IL-8 secretion in primary cultures of human bronchial epithelial cells. SA number 1: To characterize the LPA-induced IL-8 secretion in HBEpCs; SA number 2: To identify PKC isotypes and MAP Kinases that regulate LPA-induced IL-8 secretion; SA number 3: To characterize the role of phospholipase D/phosphatidic acid activation in LPA-induced IL-8 secretion in HBEpCs; SA number 4: To determine the involvement of lipid phosphate phosphatases in LPA-induced transactivation of growth factor receptors and IL-8 secretion, and SA number 5: To characterize the role of LPA as an inflammatory mediator in airways of murine model of inflammation. A better understanding of the regulation of LPA-mediated IL-8 secretion in the airway epithelium will allow development of targeted therapies to attenuate lung inflammation.
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