GLOBAL HYPOTHESIS: Our objective is to decouple obligatory postinjury splanchnic hypoperfusion from provoking systemic hyperinflammation that ultimately culminates in multiple organ failure (MOF). During the first 5 years of this project, we focused on the mechanisms involved in gut ischemia/reperfusion (I/R) induced priming of circulating neutrophils (PMNs). In the next 5 years, we plan to characterize and target intracellular signaling events involved in PMN priming and pathologic PMN- endothelial interaction in distal organs following splanchnic hypoperfusion. WORKING HYPOTHESIS: Splanchnic hypoperfusion renders the injured patient at risk for MOF by a) priming circulating PMNs for cytotoxicity (02 generation, protease release, adhesion molecule CD11b/CD18 expression) and b) stimulating distant microvascular endothelium for primed PMN adherence (E-selectin, ICAM1). While traditional therapy has concentrated on extracellular events; eg, blocking receptors (monoclonal antibodies) or nullifying cellular products (antioxidants), intervention at the level of signal transduction may prove to be more effective clinically. Mitogen- activating protein (MAP) kinase cascades are an integral component of the intracellular signaling for both PMN priming and endothelial adhesion molecule expression. More specifically, the p38 MAPK pathway appears central to both cellular responses. We hypothesize the inhibition of p38 MAPK will attenuate a) gut I/R induced PMN priming for cytodestruction and b) distant organ endothelial expression of counterligands for the primed PMN and, thereby, decouple postinjury splanchnic hypoperfusion from initiating MOF.
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