Deficient iNOS in inflammatory bowel disease intestinal microvascular endothelial cells results in increased leukocyte adhesion. Free Radic Biol Med 2000 Nov 01;29(9):881-8
Date
11/07/2000Pubmed ID
11063913DOI
10.1016/s0891-5849(00)00391-9Scopus ID
2-s2.0-0034333259 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
Microvascular endothelial cells play a key role in inflammation by undergoing activation and recruiting circulating immune cells into tissues and foci of inflammation, an early and rate-limiting step in the inflammatory process. We have previously [Binion et al., Gastroenterology112:1898-1907, 1997] shown that human intestinal microvascular endothelial cells (HIMEC) isolated from surgically resected inflammatory bowel disease (IBD) patient tissue demonstrate significantly increased leukocyte binding in vitro compared to normal HIMEC. Our studies [Binion et al., Am. J. Physiol.275 (Gastrointest. Liver Physiol. 38):G592-G603, 1998] have also demonstrated that nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) normally plays a key role in downregulating HIMEC activation and leukocyte adhesion. Using primary cultures of HIMEC derived from normal and IBD patient tissues, we sought to determine whether alterations in iNOS-derived NO production underlies leukocyte hyperadhesion in IBD. Both nonselective (N(G)-monomethyl-L-arginine) and specific (N-Iminoethyl-L-lysine) inhibitors of iNOS significantly increased leukocyte binding by normal HIMEC activated with cytokines and lipopolysaccharide (LPS), but had no effect on leukocyte adhesion by similarly activated IBD HIMEC. When compared to normal HIMEC, IBD endothelial cells had significantly decreased levels of iNOS mRNA, protein, and NO production following activation. Addition of exogenous NO by co-culture with normal HIMEC or by pharmacologic delivery with the long-acting NO donor detaNONOate restored a normal leukocyte binding pattern in the IBD HIMEC. These data suggest that loss of iNOS expression is a feature of chronically inflamed microvascular endothelial cells, which leads to enhanced leukocyte binding, potentially contributing to chronic, destructive inflammation in IBD.
Author List
Binion DG, Rafiee P, Ramanujam KS, Fu S, Fisher PJ, Rivera MT, Johnson CP, Otterson MF, Telford GL, Wilson KTAuthors
Christopher P. Johnson MD Emeritus Professor in the Surgery department at Medical College of WisconsinMary F. Otterson MS, MD Emeritus Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Cell AdhesionCells, Cultured
Endothelium, Vascular
Free Radicals
Humans
Inflammatory Bowel Diseases
Intestines
Leukocytes
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
RNA, Messenger
