lethality after intestinal ischemia and reperfusion

Abstract: Ischemia reperfusion injury is charac-terized by local and systemic inflammation leading to considerable mortality. Previously, we have re-ported that soluble T1/ST2 (sST2), a member of the IL-1 receptor gene family, inhibits LPS-in-duced macrophage proinflammatory cytokine pro-duction. Here, we report the therapeutic effect of sST2-Fc in a murine model of intestinal ischemia reperfusion-induced injury. Administration of sST2-Fc fusion protein i.v., 10 min before reper-fusion, reduced the production of TNF- dose-dependently in the intestine and in the lungs. The sST2-Fc treatment with the highest dose (100 g) resulted in inhibited vascular permeability, neutro-philia, and hemorrhage in the intestine and the lungs compared with controls treated with normal IgG. This was associated with down-regulated tissue levels of proinflammatory cytokines, markedly re-duced serum TNF- levels, and increased survival of mice from the sST2-Fc-treated group after isch-emia and reperfusion injury. The beneficial effect of sST2-Fc treatment was associated with elevated IL-10 production in intestine and lung. sST2-Fc was not able to prevent the inflammatory response associated with intestinal ischemia and reperfusion in IL-10-deficient mice, suggesting that sST2 ex-erts its anti-inflammatory effect in a IL-10-depen-dent manner. These results also demonstrate that sST2-Fc may provide a novel, complementary ap-proach in treating ischemic reperfusion injury. J