Rac2 is a member of the Rac family of GTPases commonly expressed by cells of hematopoietic origin. Our recent studies suggest that Rac2 mRNA and protein is expressed by pulmonary microvascular endothelial cells in a granular pattern within the central perinuclear region, that Rac2 regulates the vascular permeability and enhances the barrier function of normal lungs, that Rac2 is required for increases in pulmonary permeability induced by complement activation, and that endothelial Rac2 expression is regulated by TNF-a. The proposed studies will help to better understand the important roles of this GTPase in lung permeability and inflammation by testing the working hypothesis that Rac2 expressed in endothelial cells modulates fluid flux in healthy lungs and increased vascular permeability in endothelial cell injury by regulating vesicular transport and/or integrity of the endothelial cell borders, and that its activity and expression are modulated during the innate immune response.
Aim 1 will determine how Rac2 regulates fluid flux in normal lungs. Extravascular lung water will be measured, the rate of albumin accumulation will be compared in Rac2 deficient and wild type mice, which endothelial cells or other lung parenchymal cells express Rac2 will be evaluated, and whether Rac2 modulates fluid fluxes through changes in the junctional complexes or the vesicular transport system will be determined.
Aim 2 will determine how Rac2 is activated during endothelial cell injury. The role of ICAM-1 ligation, reactive oxygen species, and/or deposition of C5b-9 complexes (membrane attack complexes) in initiating Rac2 activation in vivo and in vitro will be examined, as well as the intracellular signaling pathways that lead to Rac2 activation.
Aim 3 will determine how TNF-a and other cytokines regulate Rac2. Whether TNF-a, IL-1 and interferon-g all have similar effects on endothelial Rac2 production and activation in vivo and in vitro will be assessed, as well as the role of cytokine-induced signaling pathways. Whether endothelial Rac2 is required for cytokine-induced injury in vivo and in vitro will also be determined. These studies will help to understand the role of endothelial cell Rac2 in enhancing the barrier function and in regulating permeability and other aspects of host defense during injury. ? ?
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