Sepsis accounts for approximately 751,000 hospitalizations and 215,000 deaths annually in the United States, with annual costs of nearly $17 billion. The mortality rate from severe sepsis ranges from 30-50%. Severe sepsis is often associated with profound hypotension, massive vasodilation, shock, and multiple organ failure. The mechanisms leading to the cardiovascular collapse are not fully understood. It appears that induction of nitric oxide synthesis as a result of excessive inflammatory cytokine production plays a critical role in the massive vasodilation and the depression of heart function. A number of inflammatory cytokines, particularly TNF-alpha and IL-1beta, play an important role in mediating this pathophysiological process. The MAP kinases play a crucial role in mediating the production of cytokines, including TNF-alpha and IL- 1beta. My laboratory has pioneered the role of MAP kinase phosphatases (MKP)-1 in the negative control of cytokine expression. We found that MKP-1 acts as a central negative regulator to restrain the production of TNF-alpha and IL-6 in macrophages exposed to bacterial components. Recently, we found that knockout of MKP-1 in mice resulted in dramatic increases in the production of TNF-alpha and IL-6 upon challenge with IPS. These MKP-1 -/-mice exhibited severe hypotension, profound abnormalities in lung, liver, and kidney, and a marked increase in mortality. Based on these results, we hypothesize that MKP-1 acts to prevent the over-reaction of the innate immune system to bacterial insult, and thereby maintains cardiovascular function. In the present application, we propose to study the function of MKP-1 during severe sepsis.
Our Specific Aims are: 1) To test the hypothesis that MKP-1 knockout mice are more susceptible than are wild type mice to endotoxic shock due to exacerbated inflammatory responses by both the hematopoietic cell lineage and cardiomyocytes and resulting damage to the cardiac tissues;2) To test the hypothesis that cholera toxin B subunit, a potent MKP-1-inducing agent, offers protection against LPS-induced mortality. Completion of the proposed studies will provide critical insights into the regulatory mechanisms that prevent the over-reaction of the innate immune system. More importantly, these studies may reveal novel therapeutic targets for treating sepsis and sepsis-associated shock and multiple organ failure syndrome.
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