Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity.
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.
Vallance
Bruce A
BA
Division of Gastroenterology, British Columbia's Children's Hospital, Vancouver, British Columbia, V6H 3V4. bvallance@cw.bc.ca
Dijkstra
Gerard
G
Qiu
Bosheng
B
van der Waaij
Laurens A
LA
van Goor
Harry
H
Jansen
Peter L M
PL
Mashimo
Hiroshi
H
Collins
Stephen M
SM
D000818:Animals; D018988:Bacterial Translocation; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D020397:Goblet Cells / Q000201:enzymology / Q000648:ultrastructure; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013047:Specific Pathogen-Free Organisms; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse