title: Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.
abstract: Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, The Netherlands.
authors.forename: Laurens
authors.initials: L
authors.lastname: Kruidenier
authors.forename: Ineke
authors.initials: I
authors.lastname: Kuiper
authors.forename: Wim
authors.initials: W
authors.lastname: Van Duijn
authors.forename: Marij A C
authors.initials: MA
authors.lastname: Mieremet-Ooms
authors.forename: Ruud A
authors.initials: RA
authors.lastname: van Hogezand
authors.forename: Cornelis B H W
authors.initials: CB
authors.lastname: Lamers
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D008875:Middle Aged; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008668:Metallothionein; D002374:Catalase; D009195:Peroxidase; D005979:Glutathione Peroxidase; D005978:Glutathione