Reduced sensitivity of inducible nitric oxide synthase-deficient mice to chronic colitis.
BACKGROUND
Overproduction of nitric oxide by the inducible form of nitric oxide synthase (iNOS) has been implicated in colitis. Different authors have postulated both toxic and protective effects of nitric oxide (NO) in the pathophysiology of active inflammation. The objective of this study was to examine the role of iNOS in experimental chronic colitis using iNOS-deficient mice.


METHODS
For induction of colitis, mice received three cycles of 2% of dextran sodium sulfate (DSS) (M.W. 40,000) treatment in drinking water. The degree of colonic inflammation, leukocyte infiltration, and the expression of cell adhesion molecules were determined. INOS expression and nitrotyrosine were also determined by immunohistochemistry.


RESULTS
After DSS treatment, a moderate colitis with marked cell infiltration was observed. Intense expression of iNOS was observed on infiltrating cells as well as on the colonic mucosal epithelium in these animals. In the iNOS-deficient mice, tissue damage was significantly diminished. No iNOS or nitrotyrosine staining was found in iNOS-deficient mice. The number of infiltrating cells and the expression of mucosal adressin cell adhesion molecule-1 were significantly attenuated in the DSS-treated colon of iNOS-deficient mice.


CONCLUSIONS
Induction of iNOS seems to act as a critical toxic effector molecule in the pathogenesis of chronic colonic inflammation.
Hokari
R
R
Second Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
Kato
S
S
Matsuzaki
K
K
Kuroki
M
M
Iwai
A
A
Kawaguchi
A
A
Nagao
S
S
Miyahara
T
T
Itoh
K
K
Sekizuka
E
E
Nagata
H
H
Ishii
H
H
Miura
S
S
D000818:Animals; D015815:Cell Adhesion Molecules; D002908:Chronic Disease; D003092:Colitis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D007136:Immunoglobulins / Q000378:metabolism; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D016264:Dextran Sulfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse