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Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity.
Am J Physiol Gastrointest Liver Physiol. 2004 Oct; 287(4):G865-74.AJ

Abstract

The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis.

Authors+Show Affiliations

Division of Gastroenterology, British Columbia's Children's Hospital, Vancouver, British Columbia, V6H 3V4. bvallance@cw.bc.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15217783

Citation

Vallance, Bruce A., et al. "Relative Contributions of NOS Isoforms During Experimental Colitis: Endothelial-derived NOS Maintains Mucosal Integrity." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 287, no. 4, 2004, pp. G865-74.
Vallance BA, Dijkstra G, Qiu B, et al. Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity. Am J Physiol Gastrointest Liver Physiol. 2004;287(4):G865-74.
Vallance, B. A., Dijkstra, G., Qiu, B., van der Waaij, L. A., van Goor, H., Jansen, P. L., Mashimo, H., & Collins, S. M. (2004). Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity. American Journal of Physiology. Gastrointestinal and Liver Physiology, 287(4), G865-74.
Vallance BA, et al. Relative Contributions of NOS Isoforms During Experimental Colitis: Endothelial-derived NOS Maintains Mucosal Integrity. Am J Physiol Gastrointest Liver Physiol. 2004;287(4):G865-74. PubMed PMID: 15217783.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity. AU - Vallance,Bruce A, AU - Dijkstra,Gerard, AU - Qiu,Bosheng, AU - van der Waaij,Laurens A, AU - van Goor,Harry, AU - Jansen,Peter L M, AU - Mashimo,Hiroshi, AU - Collins,Stephen M, Y1 - 2004/06/24/ PY - 2004/6/26/pubmed PY - 2004/11/9/medline PY - 2004/6/26/entrez SP - G865 EP - 74 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 287 IS - 4 N2 - The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/15217783/Relative_contributions_of_NOS_isoforms_during_experimental_colitis:_endothelial_derived_NOS_maintains_mucosal_integrity_ DB - PRIME DP - Unbound Medicine ER -