IL-18 is a unique cytokine that plays a key role in inflammation, T-cell mediated immune responses and ischemic tissue injury in the heart, lung and brain. To date, the mechanism by which IL-18 mediates ischemic injury in these organs has been attributed to its role in inflammation and neutrophil recruitment. IL-18 is also important in the pathogenesis of ischemic acute renal failure (ARF). The mechanism by which IL-18 mediates ischemic ARF, however, is independent of neutrophils. This proposal investigates the neutrophil-independent mechanisms by which IL-18 contributes to injury in ischemic ARF. Ischemic ARF is characterized by proximal tubule (PT) necrosis, known as acute tubular necrosis (ATN). Ischemic ARF is a common condition in hospitalized patients; in the intensive care unit setting, the associated mortality is 50 to 80%. A better understanding of the pathogenesis of ischemic ARF is needed to facilitate the development of interventions that shorten its course and improves survival. IL-18 may contribute to the pathogenesis of ischemic ARF by two proposed mechanisms: 1) recruitment and activation of CD4 T lymphocytes and 2) direct action on the PT cell. The following hypotheses will be investigated: 1) Caspase-1 activates IL-18 in both the renal endothelium and PT, 2) Endothelial IL-18 upregulates the expression of VCAM-1 on the endothelial surface which facilitates CD4 T cell adherence, 3) IL-18 from the PT stimulates the production of chemokines (MIP-2 and MCP-1) which attract CD4 T cells into the interstitium, contributing to ischemic injury 4) ischemia upregulates the expression of the IL-18 receptor on the PT cell surface, and 5) IL-18 acts directly on the PT to cause necrosis. Experiments will be carried out using an in vivo model (bilateral renal pedicle clamping in mice) as well as an in vitro model (freshly isolated PT exposed to hypoxia). A time course of ischemic ARF to study the activation of caspase-1, IL-18, VCAM-1, MIP-2 and MCP-1 will be performed. The pathogenic nature of these proteins in ischemic ARF will be examined in a variety of settings including caspase-1 deficient mice, treatment with VCAM-1 blocking antibody and CD4 T cell depletion. The results of these experiments will contribute to the understanding of the pathogenesis of ischemic ARF, as well as ischemia in other organs.
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