The overall objective of Project 1 is to address the critical signaling pathways by which the pro-inflammatory cytokine TNFalpha mediates the expression of the adhesion molecule, ICAM-1, in endothelial cells and thereby induces firm neutrophil (PMN) adhesion. As stable and firm ICAM-1-dependent adhesion of PMNs to endothelial cells may require rapid-onset, protein synthesis-independent ICAM-1 expression as well as delayed protein synthesis-dependent ICAM-1 expression, we will explore both the early course of its expression involving cell surface alterations in the constitutively expressed ICAM-1 in endothelial cells and the delayed expression requiring de novo protein synthesis. We will determine 1) the role of intracellular oxidant signaling by the gp91(phox) (Nox2) NADPH oxidase subunit vs. Nox4 in endothelial cells in mediating ICAM-1 expression and PMN adhesion to endothelial cells downstream of activation of specific TNFalpha receptors, 2) the central role of PKCzeta and its adaptor protein p62 in activating oxidant signaling and thereby in signaling NF-kappaB activation and ICAM-1 expression, 3) the role of the kinases, phosphoinositol 3-kinase and Akt, in signaling PKCzeta activation and thereby in inducing NF-kappaB activation and ICAM-1 expression, and 4) the role of the RhoGTPases, RhoA, Rac, and Cdc42, and downstream effector p21-activated kinase, PAK, in oxidant signaling and mediating the early-onset protein synthesis-independent component of ICAM-1 expression and PMN adhesion. Studies in endothelial cells will utilize molecular approaches to dissect the components of the signaling pathways and delineate the specific pathways mediating ICAM-1 expression, and promoting endothelial adhesivity to PMNs. These studies will be coupled to experiments in intact mouse lung in which the role of these signaling pathways will be determined in mice with specific genetic deletions. The lung studies will involve making physiological assessments of PMN sequestration and migration as well as of microvascular permeability and edema formation. With the completion of these studies, we will have a detailed understanding of the specific signaling mechanisms by which TNFalpha induces endothelial cell ICAM-1 expression and mediates inappropriate PMN adhesion and migration across the pulmonary microvessel barrier. Thus, we will be in the position to develop therapeutic strategies to block the identified specific signaling events mediating acute lung inflammatory injury.

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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