Nitric oxide and evaluation of different treatments in experimental colitis and inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder of unknown etiology of the gastrointestinal tract. Central features of IBD are increased nitric oxide (NO) generation in the gut lumen and dysfunction in regulation of leukocyte recruitment from the blood stream towards the affected tissue.

This study aimed to investigate NO and the role of collagen-binding α2β1 integrin in IBD and experimental colitis, with special reference to how NO is synthesised, how NO affects gut motility, how rectal NO levels can be a used to identify corticosteroid refractory IBD patients, and to compare anti-integrin treatment to current treatment regimes in IBD.

The results show that expression of inducible NO synthase (iNOS) is increased in inflamed colonic tissue in both animal and man, and can be a useful biomarker for colonic inflammation, that we today are lacking. The induced overproduction of NO is likely to be responsible for the decreased motility in colitis where NO is suggested to exert a suppressive tone on colonic contractility, which is reversed by blockade of NO synthase. Results show that low (<1000 ppb) initial rectal NO levels upon onset of flare, were distinct to the patient with a steroid-refractory disease, later subjected to colectomy. Thus rectal NO levels could be a useful biomarker of treatment response in IBD.

An alleviating action of the collagen binding α2β1 integrin in experimental colitis is demonstrated and suggests that this effect is mediated by inhibition of neutrophil migration and activation. The studies show that anti-integrin treatment through rectal administration of anti-α2 or anti-α4 integrin antibodies reduced clinical and histological signs of colitis in mice.

The protective effects against colitis seen after anti-integrin treatment are favorable and have therapeutic potential beyond current treatment regimens with 5-ASA, betamethasone, immunomodulators and cytostatic compounds. Local administration of function-blocking antibodies against integrin α2β1 may provide novel avenues to treat inflammatory bowel disease.

List of scientific papers

I. Lundberg S, Holst M, Hellstrom PM (2006). Expression of iNOS mRNA associated with suppression of colonic contraction in rat colitis. Acta Physiol (Oxf). 187(4): 489-94.
https://pubmed.ncbi.nlm.nih.gov/16866779

II. Ljung T, Lundberg S, Varsanyi M, Johansson C, Schmidt PT, Herulf M, Lundberg JO, Hellstrom PM (2006). Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders. World J Gastroenterol. 12(21): 3386-92.
https://pubmed.ncbi.nlm.nih.gov/16733856

III. Lundberg S, Lindholm J, Lindbom L, Hellstrom PM, Werr J (2006). Integrin alpha2beta1 regulates neutrophil recruitment and inflammatory activity in experimental colitis in mice. Inflamm Bowel Dis. 12(3): 172-7.
https://pubmed.ncbi.nlm.nih.gov/16534417

IV. Lundberg S, Lindholm J, Lindbom L, Hellstrom PM, Werr J (2006). Integrin-blockade compared to conventional treatment in experimental colitis. [Manuscript]