Skip to main content
SpringerLink
Log in

Increased Nitric Oxide Production and Inducible Nitric Oxide Synthase Activity in Colonic Mucosa of Patients with Active Ulcerative Colitis and Crohn's Disease

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

It is postulated that an enhanced production ofnitric oxide by inflamed intestine plays a role in thepathophysiology of active inflammatory bowel disease. Inthis study, systemic NOx concentrations and colonic nitric oxide synthase activity weredetermined in patients with ulcerative colitis orCrohn's disease. The relationship between these twoparameters and disease activity, as well as differences in nitric oxide synthase activity betweenulcerative colitis and Crohn's disease, were areas ofspecific focus. Patients with active ulcerative colitisand Crohn's disease had significantly elevated plasma NOx concentrations; a positivecorrelation was found between NOx values andinducible nitric oxide synthase activities in the activemucosa of these patients. In active ulcerative colitis,levels of inducible nitric oxide synthase were significantlyelevated in both normal and inflamed mucosa, althoughinducible nitric oxide synthase activity was higher inthe latter. These colonic inducible nitric oxidesynthase activities correlated well with the results ofendoscopic and histologic grading of inflammation. Therewas no increase in constitutive nitric oxide synthaseactivity in patients with active ulcerative colitis. However, constitutive nitric oxidesynthase activity was significantly increased in theinflamed mucosa in patients with Crohn's disease. InCrohn's disease, elevated inducible nitric oxidesynthase activity was found in both normal and inflamedmucosa, with no significant difference between thetissues. Such differences in nitric oxide production inthe colonic mucosa possibly reflect the significant differences in the pathophysiology andcharacteristic clinical features between ulcerativecolitis and Crohn's disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329:2002-2012, 1993

    Google Scholar 

  2. Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 6:3051-3064, 1992

    Google Scholar 

  3. Stuehr DJ, Nathan CF: Nitric oxide: A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 169:1543-1555, 1989

    Google Scholar 

  4. Kurose I, Miura S, Fukumura D, Yonei Y, Saito H, Tada S, Suematsu M, Tsuchiya M: Nitric oxide mediates Kupffer cell-induced reduction of mitochondrial energization in hepatoma cells: A comparison with oxidative burst. Cancer Res 53:2676-2682, 1993

    Google Scholar 

  5. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA: Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620-1625, 1990

    Google Scholar 

  6. Roediger WEW, Lawson MJ, Radcliffe BC: Nitrite from inflammatory cells: A cancer risk factor in ulcerative colitis? Dis Colon Rectum 33:1034-1036, 1990

    Google Scholar 

  7. Middleton SJ, Shorthouse M, Hunter JO: Increased nitric oxide synthesis in ulcerative colitis. Lancet 341:465-466, 1993

    Google Scholar 

  8. Miller MJS, Sadowska-Krowicka H, Chotinaruemol S, Kakkis JL, Clark DA: Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther 264:11-16, 1993

    Google Scholar 

  9. Yamada T, Sartor RB, Marshall S, Specian RD, Grisham MB: Mucosal injury and inflammation in a model of granulomatous colitis in rats. Gastroenterology 104:759-777, 1993

    Google Scholar 

  10. Boughton-Smith NK, Evans SM, Hawkey CJ, Cole AT, Balsitis M, Whittle BJR, Moncada S: Nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Lancet 342:338-340, 1993

    Google Scholar 

  11. Grisham MB, Specian RD, Zimmerman TE: Effects of nitric oxide synthase inhibition on the pathophysiology observed in a model of chronic granulomatous colitis. J Pharmacol Exp Ther 271:1114-1121, 1994

    Google Scholar 

  12. Kirsner JB, Shorter RG: Inflammatory Bowel Disease, ed 3. Philadelphia, Lea & Febiger, 1988

    Google Scholar 

  13. Rachmilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z, Podolsky DK: Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36:718-723, 1995

    Google Scholar 

  14. Hibi T, Ohara M, Kobayashi K, Brown WR, Toda K, Takaishi H, Hosoda Y, Hayashi A, Iwao Y, Watanabe M, Aiso S, Kawai Y, Tsuchiya M: Enzyme linked immunosorbent assay (ELISA) and immunoprecipitation studies on anti-goblet cell antibody using a mucin producing cell line in patients with inflammatory bowel disease. Gut 35:224-230, 1994

    Google Scholar 

  15. Best WR, Becktel JM, Singelton JW, Kern F, Jr: Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 70:439-444, 1976

    Google Scholar 

  16. Rutegard I, Ahsgren L, Stenling R, Nilsson T: A simple index for assessment of disease activity in patients with ulcerative colitis. Hepatogastroenterology 37:110-112, 1990

    Google Scholar 

  17. Wardle TD, Hall L, Turnberg LA: Use of coculture of colonic mucosal biopsies to investigate the release of eicosanoids by inflamed and uninflamed mucosa from patients with inflammatory bowel disease. Gut 33:1644-1651, 1992

    Google Scholar 

  18. Granger DL, Hibbs JB Jr, Perfect JR, Durack DT: Metabolic fare of L-arginine in relation to microbiostatic capacity of murine macrophages. J Clin Invest 85:264-273, 1990

    Google Scholar 

  19. Knowles RG, Merrett M, Salter M, Moncada S: Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J 270:833-836, 1990

    Google Scholar 

  20. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA: Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 29:669-674, 1988

    Google Scholar 

  21. Grisham MB, Miles AM, Owens M, Johnson GG: Molecular, biochemical and cellular characterization of the inducible nitrite oxide synthase in circulating vs. extravasated polymorphonuclear leukocytes (PMNs). Gastroenterology 106:A693, 1994

    Google Scholar 

  22. Sartor RB: Cytokines in intestinal inflammation: Pathophysiological and clinical considerations. Gastroenterology 106:533-539, 1994

    Google Scholar 

  23. Tepperman BL, Brown JF, Whittle BJR: Nitric oxide synthase induction and intestinal epithelial cell viability in rats. Am J Physiol 265:G214-G218, 1993

    Google Scholar 

  24. Dignass AU, Podolsky DK, Rachmilewitz D: NOx generation by cultured small intestinal epithelial cells. Dig Dig Sci 40:1859-1865, 1995

    Google Scholar 

  25. Reynolds PD, Middleton SJ, Hunter JO, Facer P, Bishop A, Evans T, Polak JM: High expression of iNOS in colonic mucosa in ulcerative colitis. Gastroenterology 108:A903, 1995

    Google Scholar 

  26. Singer II, Kawka DW, Scott S, Weidner JR, Mumford RA, Riehl TE, Stenson WF: Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology 111:871-885, 1996

    Google Scholar 

  27. Belenky SN, Robbins RA, Rennard SI, Gossman GL, Nelson KJ, Rubinstein I: Inhibitors of nitric oxide synthase attenuate human neutrophil chemotaxis in vitro. J Lab Clin Med 122:388-394, 1993

    Google Scholar 

  28. Belenky SN, Robbins RA, Rubinstein I: Nitric oxide synthase inhibitors attenuate human monocyte chemotaxis in vitro. J Leukoc Biol 53:498-503, 1993

    Google Scholar 

  29. Granger DL, Taintor RR, Cook JL, Hibbs JB: Injury of neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration. J Clin Invest 65:357-370, 1980

    Google Scholar 

  30. Hibbs JB, Taintor RR, Vavrin Z: Iron depletion: Possible cause of tumor cell cytotoxicity induced by activated macrophages. Biochem Biophys Res Commun 123:716-723, 1984

    Google Scholar 

  31. Kwon NS, Stuehr DJ, Nathan CF: Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J Exp Med 174:761-767, 1991

    Google Scholar 

  32. Sankey EA, Dhillon AP, Anthony A, Wakefield AJ, Sim R, More L, Hudson M, Sawyerr AM, Pounder RE: Early mucosal changes in Crohn's disease. Gut 34:375-381, 1993

    Google Scholar 

  33. Baldassano RN, Schreiber S, Johnston RB Jr, Fu RD, Muraki T, MacDermott RP: Crohn's disease monocytes are primed for accentuated release of toxic oxygen metabolites. Gastroenterology 105:60-66, 1993

    Google Scholar 

  34. Suematsu M, Suzuki M, Kitahora T, Miura S, Suzuki K, Hibi T, Watanabe M, Nagata H, Asakura H, Tsuchiya M: Increased respiratory burst of leukocytes in inflammatory bowel diseases--The analysis of free radical generation by using chemiluminescence probe. J Clin Lab Immunol 24:125-128, 1987

    Google Scholar 

Download references

Authors
  1. Hiroyuki Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soichiro Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takeharu Shigematsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuyuki Ohkubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshikazu Tsuzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Iwao Kurose
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hajime Higuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasutada Akiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryota Hokari
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masahiko Hirokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Serizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiromasa Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kimura, H., Miura, S., Shigematsu, T. et al. Increased Nitric Oxide Production and Inducible Nitric Oxide Synthase Activity in Colonic Mucosa of Patients with Active Ulcerative Colitis and Crohn's Disease. Dig Dis Sci 42, 1047–1054 (1997). https://doi.org/10.1023/A:1018849405922

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018849405922

Search

Navigation