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MUCOSAL BIOLOGY

IL-1 alters hemodynamics in newborn intestine: role of endothelin

Center for Cell and Vascular Biology, Columbus Children's Research Institute and Department of Pediatrics, The Ohio State University, Columbus, Ohio

Submitted 23 January 2006 ; accepted in final form 6 April 2006

Studies were carried out to determine the effects of IL-1 on newborn intestinal hemodynamics. IL-1 increased the release of ET-1 by primary endothelial cells in a dose-dependent manner; as well, it reduced expression of the endothelin (ET) type B (ET_B) receptor on endothelial cells and increased expression of the ET type A (ET_A) receptor on vascular smooth muscle cells. IL-1 increased endothelial cell endothelial nitric oxide (NO) synthase (eNOS) expression but did not enhance eNOS activity as evidenced by release of NO_x into conditioned medium in response to acetylcholine or shear stress. The effects of IL-1 on flow-induced dilation were evaluated in terminal mesenteric arteries in vitro. Pretreatment with IL-1 (1 ng; 4 h) significantly attenuated vasodilation in response to flow rates of 100 and 200 µl/min. This effect was mediated, in part, by the endothelin ET_A receptor; thus selective blockade of ET_A receptors with BQ610 nearly restored flow-induced dilation. In contrast, exogenous ET-1 only shifted the diameter-flow curve downward without altering the percent vasodilation in response to flow. The effects of IL-1 on ileal oxygenation were then studied using in vivo gut loops. Intramesenteric artery infusion of IL-1 upstream of the gut loop caused ileal vasoconstriction and reduced the arterial-venous O₂ difference across the gut loop; consequently, it reduced ileal oxygenation by 60%. This effect was significantly attenuated by pretreatment with BQ610. These data support a linkage between the proinflammatory cytokine IL-1 and vascular dysfunction within the intestinal circulation, mediated, at least in part, by the ET system.

newborn intestine; necrotizing enterocolitis; intestinal blood flow; intestinal oxygenation

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