LPS-induced oxidant signaling by PMN NADPH oxidase may play a pivotal role in acute lung injury. Project 4 tests the central hypothesis that there exists a pro-inflammatory interaction between activated PMNs and naive endothelial cells that results in endothelial cell activation (defined as up-regulation of NF-KB and ICAM-1 and TLR4 expression) and that this interaction is a key determinant of the pathogenesis of acute lung injury.
Aim #1 will test the hypothesis that oxidants derived from activation of the PMN NADPH oxidase complex signal the activation of NF-KB in endothelial cells, and thereby up-regulate NF-KB-dependent inflammatory pathways in endothelial cells.
Aim #2 will determine the role of PMN NADPH oxidase-derived transcellular oxidant signaling in inducing ICAM-1 expression in endothelial cells and in thereby promoting endothelial PMN hyperadhesivity.
Aim #3 will test the hypothesis that PMN-derived oxidant signaling up-regulates the expression of the LPS receptor TLR4 in endothelial cells and is a requirement for LPS induction of endothelial injury.
Aim #4 will determine the role of endothelial adherens junction (AJ) disassembly induced by PMN activation as a key mechanism signaling the down-modulation of NF-KB activation and ICAM-1 and TLR4 expression.
Aim #5 will test in PMNs the role of lysophosphatidylcholine (LPC) and the activation of its heptahelical G protein-coupled receptor, G2A, in down-regulating PMN activation by inhibition of NADPH oxidase activation, and thereby preventing the PMN/ endothelial cell crosstalk-dependent endothelial injury. These data will provide significant new insights into the mechanisms of acute lung injury and pathways that may prevent or reverse this lung injury. Furthermore, we believe that it may be possible with a new understanding of this transcellular cross-talk to block inappropriate PMN-endothelial cell interactions and PMN-mediated acute lung injury by interfering with specific signaling pathways.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Illinois at Chicago
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