Depleted mucosal antioxidant defences in inflammatory bowel disease

Buffinton, Gary D.; Doe, William F.

doi:10.1016/0891-5849(95)94362-h

Cited by 225 publications

(118 citation statements)

References 24 publications

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“…IBD is a multifactorial disease where activation of inflammatory cells are thought to play a key role for its development, however the role of ROS and subsequent oxidative stress as a pathological factor for IBD has not been well defined. Indeed, a large number of previous studies examining the status of antioxidants in mucosa from patients and experimental animal models of colitis have reported a decrease in the levels of antioxidants, including that of GSH (Buffinton and Doe, 1995;Holmes et al, 1998;Lih-Brody et al, 1996;Millar et al, 1996;Sá nchez de Medina et al, 1996;Sido et al, 1998;Zea-Iriarte et al, 1996). However, the temporal relationship and functional consequences of mucosal GSH depletion in the development of colitis have not been clearly established.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, the time dependent relationship between mucosal GSH levels and injury score during the acute phase of colitis establish a progressive fall of GSH levels that is accompanied by a worsening of injury induced by TNBSϩethanol. Although it has been known both in humans and rats that mucosal GSH becomes depleted in colitis (Buffinton et al, 1995;Holmes et al, 1998;Lih-Brody et al, 1996;Millar et al, 1996;Sá nchez de Medina et al, 1996;Sido et al, 1998;Zea-Iriarte et al, 1996), its pathophysiological relevance in the course of colitis has not been definitively established. Our work, however, reveal that the depletion of mucosal GSH is an event that occurs early during the induction of colitis, as soon as TNBS reaches cellular GSH.…”

Section: Discussionmentioning

confidence: 99%

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Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Ardite

Sans

Panés

et al. 2000

Laboratory Investigation

106

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SUMMARY:Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBSϩethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBSϩethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBSϩethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBSϩethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBSϩethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60 -70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBSϩethanol-induced injury. Interestingly, GSH levels in TNBSϩethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of ␥-glutamylcysteine synthetase (␥-GCS) activity due to an induction of ␥-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD. (Lab Invest 2000, 80:735-744).I nflammatory bowel disease (IBD) is a chronic inflammatory disorder whose etiology is not completely understood. Several factors are recognized to contribute to its development including an overgeneration of reactive oxygen species (ROS). Production of ROS from several sources initiate a cytotoxic cascade of events that culminate in cell death. Thus, stimulated inflammatory cells present in the inflamed mucosa are capable of producing superoxide anion and hydrogen peroxide (Harris et al, 1992;McKenzie et al, 1996;Simmonds and Rampton, 1993).The xantine oxidase pathway and the oxidation of arachidonic acid in colonocytes constitute additional sources of ROS (Biemond et al, 1988;Markowitz et al, 1988;Sedghi et al, 1993). The interaction of these species with specific vascular or interstitial components yield potent chemoattractants for inflammatory phagocytes, establishing a self-amplifying cycle of ROS production that may overwhelm defense strategies resulting in tissue damage (Lewis et al, 1988;Shingu and ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Ardite

Sans

Panés

et al. 2000

Laboratory Investigation

106

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“…[1][2][3][4][5] The oxidative stress through an excessive release of reactive oxygen species (ROS) has been proposed to play a key role in IBD pathogenesis. 6,7) Considering this, the use of antioxidant compounds may be useful in limiting damage in IBD. In fact, it has been proposed that antioxidant activity may be responsible for the beneficial effects showed by 5-aminosalycilate derivatives in human IBD.…”

mentioning

confidence: 99%

Intestinal Anti-inflammatory Activity of Coumarin and 4-Hydroxycoumarin in the Trinitrobenzenesulphonic Acid Model of Rat Colitis

Luchini

Rodrigues-Orsi

Cestari

et al. 2008

Biological & Pharmaceutical Bulletin

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Coumarins represent an important class of phenolic compounds with multiple biological activities, including inhibition of lipidic peroxidation and neutrophil-dependent anion superoxide generation, anti-inflammatory and immunosuppressor actions. All of these proprieties are essential for that a drug may be used in the treatment of inflammatory bowel disease. The present study examined intestinal anti-inflammatory activity of coumarin and its derivative, the 4-hydroxycoumarin on experimental ulcerative colitis in rats. This was performed in two different experimental settings, i.e. when the colonic mucosa is intact or when the mucosa is in process of recovery after an initial insult. The results obtained revealed that the coumarin and 4-hydroxycoumarin, at doses of 5 and 25 mg/kg, significantly attenuated the colonic damage induced by trinitrobenzenesulphonic acid (TNBS) in both situations, as evidenced macroscopically, microscopically and biochemically. This effect was related to an improvement in the colonic oxidative status, since coumarin and 4-hydroxycoumarin prevented the glutathione depletion that occurred as a consequence of the colonic inflammation.

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“…In IBD, oxidative stress plays a role in disease initiation and progression (Kruidenier & Verspaget, 2002). Reactive oxygen species (ROS) attack the cellular macromolecules, thus disrupting epithelial cell integrity and hindering mucosal recovery, especially in case of impaired endogenous defense systems (Buffinton & Doe, 1995). In this work, acetic acid induced ROS formation is inhibited by the methanol fraction as it is proved as a good antioxidant.…”

Section: Resultsmentioning

confidence: 96%