Inducible nitric oxide synthase expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion. Binion, David G., Sidong Fu, Kalathur S. Ramanujam, Yuh Cherng Chai, Raed A. Dweik, Judith A. Drazba, Justin G. Wade, Nicholas P. Ziats, Serpil C. Erzurum and Keith T. Wilson. 1Division of Gastroenterology and Hepatology, Digestive Disease Center and Cardiovascular Research Center, Froedtert Memorial Lutheran Hospital and The Medical College of Wisconsin, Milwaukee, Wisconsin 53226; 2Division of Gastroenterology, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; 3Departments of Cell Biology, 4Cancer Biology, and 5Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195; and 6The Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
APStracts 5:0187G, 1998.
Increased nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) has been associated with intestinal inflammation, including human inflammatory bowel disease (IBD). However, NO can downregulate endothelial activation and leukocyte adhesion, critical steps in the inflammatory response. Using primary cultures of human intestinal microvascular endothelial cells (HIMEC), we determined the role of NO in the regulation of HIMEC activation and interaction with leukocytes. Both nonselective (NG-monomethyl-L-arginine) and specific (N-Iminoethyl-L-lysine) competitive inhibitors of iNOS significantly increased binding of leukocytes by HIMEC activated with cytokines and lipopolysaccharide. Increased adhesion was reversible with the NOS substrate, L-arginine, and not observed in human umbilical vein endothelial cells (HUVEC). Activation of HIMEC significantly upregulated HIMEC iNOS expression and NO production. NOS inhibitors did not augment cell adhesion molecule levels in activated HIMEC, but did result in sustained increases in intracellular reactive oxygen species. In addition, antioxidant compounds reversed the effect of NOS inhibitors on HIMEC-leukocyte interaction. Taken together, these data suggest that following HIMEC activation, iNOS-derived NO is an endogenous antioxidant, downregulating leukocyte binding and potentially, intestinal inflammation. 

Received 23 April 1998; accepted in final form 1 July 1998.
APS Manuscript Number G163-8.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 30 July 1998