ENDOTHELIAL CELL RESPONSES TO SHOCK AND TRAUMA

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Ischemic (hypoxic) cell injury underlies tissue damage in diverse clinical disorders. Increasing evidence indicates that additional tissue damage follows reoxygenation (reperfusion) of ischemic tissue. Cell death following ischemia may involve activation of a intrinsic cell [suicide] program leading to apoptosis. Reperfusion injury may result from activation of an inflammatory cascade, triggered by signals generated by ischemia or following reperfusion, leading to apoptosis. Understanding the molecular basis of cellular activation/apoptosis in hypoxia/reoxygenation injury may suggest new approaches to therapy of the associated major clinical disorders. The applicant postulates that there are several signaling pathways involved in the endothelial cell s response to hypoxia/reoxygenation. The applicant hypothesizes that the stress-activated protein kinase and p38 kinase (SAPK/p38) pathways are involved in the activation of pro-inflammatory responses, and, along with p53 protein promote apoptosis. In contrast, the NF-kB pathway is required for the induction of cytoprotective pathways that is anti- apoptotic as well as pro-inflammatory. The applicant suggests that the SAPK/p38 pathways or the p53 protein may be an attractive target for hypoxia/reoxygenation induced injury, where as inhibition of the NF-kB signaling pathway alone may compromise endothelial cell survival by preventing the induction of cytoprotective proteins. The overall goal of this application is to elucidate the pathways and genes that promote survival and those that activate pro-inflammatory or pro-apoptotic responses in endothelial cells during hypoxia/reoxygenation. The specific aims in this proposal are thus: 1. to determine the expression and regulation of cytoprotective proteins in endothelial cells during hypoxia/reoxygenation; 2. to determine the role of NF-kB in the induction of pro-inflammatory and cytoprotective genes in endothelial cells during hypoxia/reoxygenation; 3. to define the role of SAPK/p35 kinase pathways in pro-inflammatory and pro-apoptotic responses to endothelial cells in hypoxia/reoxygenation; 4. to determine the mechanisms that regulate interleukin-8 gene expression in endothelial cells during hypoxia/reoxygenation; and 5. to determine the role of the p53 protein in hypoxia induced endothelial cell apoptosis.