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Nitric oxide in normal and inflamed human colon

Anders Perner  


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Accepted by: Faculty of Health Science University of Copenhagen
Defended on: October 12, 2001
Official opponents: Niels Bindslev , Lars Fändriks , Brendan Whittle
Tutors: Jorgen Rask-Madsen

Published in the PhD Database: February 16, 2004


English abstract
In human colitis, the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS) is greatly increased in the inflamed mucosa, but the pathophysiological role of NO remains speculative. The purpose of this review is to discuss the finding of extreme colonic output of NO in the absence of mucosal injury in patients with collagenous colitis.
In patients with collagenous colitis and severe ulcerative colitis, there were no differences in colonic output of NO or expression of iNOS in biopsy specimens from the colonic mucosa. Nitrotyrosine, which is a marker of nitrosative stress, was markedly expressed only in ulcerative colitis, suggesting that reactive nitrogen species, rather than NO per se, contribute to mucosal injury.
The high expression of iNOS at the luminal border of the colonic epithelium in patients with colitis is compatible with the notion that a luminal factor may be responsible for the induction of iNOS.
In the inflamed colon, NO may act as a secretagogue, because output of NO and secretion of fluid were reduced by topical inhibition of NOS by L-NMMA in perfusion studies of whole colon in patients with collagenous colitis.
While therapeutic actions against iNOS may reduce nitrotyrosine-associated damage and diarrhoea in colonic inflammation, the consequences for mucosal micro-circulation, recruitment of neutrophils and host defence are difficult to predict. Further experimental work needs to be done before testing modulators of NO bioavailability in patients with chronic inflammatory bowel disorders.



Danish abstract
Ved inflammation i tyktarmen øges slimhindens produktion af nitrogenoxid (NO), og ekspressionen af inducérbar NO syntase (iNOS) er øget i biopsier fra colonslimhinden, men betydningen af disse fund er endnu uafklaret. Denne oversigt diskuterer betydningen af øget NO produktion ved kollagen colitis, som er karakteriseret ved vandig diaré uden destruktiv inflammation.
I kvantitative studier af NO produktionen i colon og ekspressionen af iNOS i colonbiopsier observeredes forhøjede værdier både hos patienter med kollagen colitis og svær colitis ulcerosa. Endvidere fandtes øget ekspression af nitrotyrosin ved colitis ulcerosa. Det er derfor sandsynligt at nitrotyrosin og reaktive nitrogen radikaler, men ikke NO i sig selv, bidrager til slimhinde beskadigelse i den inflammerede colon.
Ekspressionen af iNOS observeredes i colonepitelet tæt ved den luminale membran hos patienter med colitis. Fundet er foreneligt med hypotese om, at luminale faktorer inducerer iNOS i colonslimhinden. Endvidere er det sandsynligt, at NO bidrager til øget sekretion af væske fra den inflammerede slimhinde, da både produktionen af NO og sekretionen af væske reduceredes ved hæmning af NO syntase med L-NMMA i den væskeperfunderede colon hos patienter med kollagen colitis.
Mens hæmning af iNOS må forventes at reducere nitrotyrosin-associeret slimhinde destruktion og diaré i den inflammerede colon, er det vanskelige at forudsige konsekvenserne for slimhindens gennemblødning, infiltration af neutrofile granulocytter og barriere funktion. Klinisk afprøvning af NO modulerende lægemidler i behandlingen af patienter med kronisk inflammatorisk tarmsygdom må derfor afvente resultaterne af yderligere eksperimentelle undersøgelser.