Delineation of hypoxia versus inflammatory contributions to tissue injury by attenuation of G-alpha-i signaling (93.7)

Abstract

Abstract The complement dependent pathology resulting from mesenteric ischemia/reperfusion insult instigates tissue injury in mesenteric and systemic organs. In this study the contribution of G-protein receptor signaling through G[alpha]i to stages of tissue injury is delineated. Global G[alpha]i inhibition, by PTX, attenuated mesenteric injury and production of lipid modulators such as leukotriene B4. Systemic inflammation was inhibited as assessed by lung tissue injury scores and monitoring cellular infiltrates. To delineate the role of G[alpha]i signaling in mesenteric versus systemic inflammatory responses, an inhibitor of pulmonary inflammatory chemotactic G[alpha]i signaling, anti-CXCR2 was used. As expected PTX and anti-CXCR2, abrogated pulmonary inflammation. In contrast, anti-CXCR2 was not effective in mitigating mesenteric injury. The results from global versus specific G[alpha]i inhibition in local and systemic injury indicate multiple mechanisms by which G[alpha]i signaling facilitate tissue injury. The G[alpha]i linked signaling effects of complement activation and chemokine induced migratory control are distinct and can be mitigated independently. Delineating which signals govern particular components of tissue injury will be useful in developing therapeutics which can control specific deleterious aspects of systemic inflammation after trauma while maintaining the protective aspects of complement activation.