PHOSPHATIDIC-ACID SIGNALING MEDIATES LUNG CYTOKINE EXPRESSION AND LUNG INFLAMMATORY INJURY AFTER HEMORRHAGE IN MICE

Because phosphatidic acid (PA) pathway signaling may mediate many basi c reactions involving cytokine-dependent responses, we investigated th e effects of CT15O1R, a functional inhibitor of the enzyme lysophospha tidic acid acyltransferase (LPAAT) which converts lysophosphatidic aci d (Lyse-PA) to PA. We found that CT15O1R treatment not only prevented hypoxia-induced PA increases and lyse-PA consumption in human neutroph ils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT15O1R treatment prevented increases in mRNA levels and protein production of a variety of proin flammatory cytokines in multiple lung cell populations after blood los s and resuscitation. Our results indicate the fundamental role of PA m etabolism in the development of acute inflammatory lung injury after b lood loss.