Oxygen radicals in ulcerative colitis.
This article reviews the pathophysiologic concept that superoxide and hydrogen peroxide, generated by activated leukocytes, together with low-molecular-weight chelate iron derived from fecal sources and from denatured hemoglobin, amplify the inflammatory response and subsequent mucosal damage in patients with active episodes of ulcerative colitis. The putative pathogenic mechanisms reviewed are as follows: (1) Dietary iron is concentrated in fecal material owing to normally limited iron absorption. (2) Mucosal bleeding, characteristic of ulcerative colitis, as well as supplemental oral iron therapy for chronic anemia, further conspire to maintain or elevate mucosal iron concentration in colitis. (3) Fenton chemistry, driven especially by leukocyte-generated superoxide and hydrogen peroxide, leads to formation of hydroxyl radicals. (4) The resultant oxidative stress leads to the extension and propagation of crypt abscesses, either through direct membrane disruption by lipid peroxidation or through generation of secondary toxic oxidants such as chloramines. (5) Chemotactic products of lipid peroxidation, including 4-hydroxynonenal, provide positive feedback to accelerate this inflammatory/oxidative process, leading to acute exacerbations of the disease. (6) Other oxidized products, such as oxidized tryptophan metabolites, created by free radical mechanisms in or near the mucosa, may act as carcinogens or tumor promotors that contribute to the exceedingly high incidence of colon carcinoma in patients suffering from chronic ulcerative colitis. In this way, self-sustaining cycles of oxidant formation may amplify flare-ups of inflammation and mucosal injury in ulcerative colitis. This concept, if proved correct by subsequent research, would provide a rationale for several novel clinical approaches to the management of ulcerative colitis, including use of SOD mimetics, iron chelators, and chain-breaking antioxidants.
Babbs
C F
CF
Biomedical Engineering Center, Purdue University, West Lafayette, IN 47907.
D000975:Antioxidants / Q000627:therapeutic use; D002273:Carcinogens / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D012460:Sulfasalazine / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D002273:Carcinogens; D005609:Free Radicals; D013481:Superoxides; D012460:Sulfasalazine; D007501:Iron; D013482:Superoxide Dismutase; D010100:Oxygen