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.

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine

“…ClCa4 is considered to be an important molecule for the induction of diarrhea in cystic fibrosis (19). Gpx2 is a marker for the colonic inflammation that occurs in experimental colitis and inflammatory bowel diseases (20)(21)(22). It has been suggested that all of these molecules are involved in the pathogenesis of inflammatory changes in the intestine.…”

The effect of progesterone in the prevention of the chemically induced experimental colitis in rats

“…There are studies in the literature that reports inflammatory cytokines such as TNF-α and IL-1 play role in the etiology of IBD [11][12][13][14] . TNF-α is the most important cytokine in inflammatory process.…”

“…MPO, MDA, NO, Caspase-3, IL-6 and TNF-α were analyzed. The tissues were rinsed with serum physiologic for the biochemical analysis and then weighted and homogenized using the method by previously described 12 . Tissue samples (distal colon) were obtained from the rats for biochemical examination.…”

“…The measurements of MPO activity were performed by the method used by Kruidener et al 12 . The tissue was homogenized and incubated in 0.5% hexadecyl-trimethylammonium bromide (pH 5.5) and 0.026% ortho-dianisidinedihydrochloride and plus 0.018% H2O2 was added.…”

COMPARISON OF SELECTIVE AND NON SELECTIVE CYCLO-OXYGENASE 2 INHIBITORS IN EXPERIMENTAL COLITIS EXACERBATION: role of leukotriene B4 and superoxide dismutase

“…Excessive liberation of RONS by polymorphonuclear cells is considered the main mechanism for colonic lesion in ulcerative colitis (UC), where accentuated lipid peroxidation occurs (48) . It has also been suggested that imbalanced and inefficient endogenous antioxidant response, especially attributed to SOD dual role acting as superoxide anion scavenger and an H 2 O 2 producer, may contribute to both the pathogenesis and the perpetuation of the inflammatory processes (27) . Therefore, the aim of the present study is to assess celecoxib, ketoprofen, and other NSAIDs effects in experimental colitis, verify which NSAIDs exacerbate the disease and contribute to the understanding of the mechanisms responsible for colitis reactivation.…”