Septic shock is a leading cause of death in the intensive care unit. A major hurdle in the clinical management of septic shock is the redundancy of mediators involved its pathophysiology, and the inability to inhibit multiple mediators simultaneously. NF-KappaB plays a crucial role in LPS- or cytokine-activated promoter activity of over 100 genes, many of which play important roles in septic pathophysiology. NF-KappaB could be an ideal target for the development of more effective therapeutic intervention for septic shock. However, two critical questions remain to be answered. First, how critical is NF-KB in mediating the in vivo expression of multiple proinflammatory genes induced by bacterial endotoxin? Second, is blocking NF-KappaB pathway beneficial or detrimental, and when and where to block this pathway, if it is proven to be beneficial? The goal of this application is to address these two questions. Our hypotheses are that NF-KappaB is a central common pathway in LPS-induced multiple proinflammatory gene expression and LPS-triggered septic pathophysioiogy, and that endothelial-selective blockade of NF-KappaB activation is beneficial to the prognosis of septic shock. We will generate two double transgenic mouse lines that conditionally overexpress the degradation-resistant l-KappaBalpha (I-Kappabalpha-mt), a potent inhibitor of NF-KappaB activation, selectively in endothelial cells (VecadrtTA/I-Kappabalphamt) and non-selectively in all cell types (CMVrtTA/I-Kappabalphamt) using a tetracycline-regulated gene expression system. We will study gene expression profiles of wild type and of CMVrtTA/I-KappaBalphamt mice after being challenged with LPS using microarray technique to define the in vivo function of NF-KappaB in mediating multiple proinflammatory gene expression. We will define the mechanistic role of NF-KappaB in septic pathophysiology. We will compare the efficacy of endothelial versus universal overexpression of I-KappaBalphamt in inhibiting multiple proinflammatory gene expression, in ameliorating septic pathophysiology. We will monitor and compare the mortality of wild type, VecadrtTA/I-KappaBalphamt and CMVrtTA/I-KBcmt mice in LPS- and CLP-induced septic shock models. We will study the effects of endothelial selective versus universal blockade of NF-KappaB activation on host defense functions against bacterial pathogens (bacterial clearance, macrophage or PMN phagocytosis). Results from our studies will provide an experimental basis and rationale for targeting NF-KappaB pathway as a novel therapeutic strategy for the treatment of septic shock.
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