Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease.

McKenzie, Sara; Baker, Mark S.; Buffinton, Gary D.; Doe, William F.

doi:10.1172/jci118757

Cited by 320 publications

(221 citation statements)

References 39 publications

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“…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 Nobunaga 1984;Zimmerman et al, 1990).…”

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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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: 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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“…To investigate the possible therapeutic effects of garlic in the treatment of IBD patients, whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated in the presence of various concentrations of garlic extract and the effect on leukocyte cytokine production was determined in vitro using multiparameter flow cytometry. Whole blood was used because bleeding into the bowel is not uncommon in IBD patients (1) and whole blood contains more of the cellular components present in the inflammatory bowel, e.g., neutrophils, which are a source of several cytokines (10).…”

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confidence: 99%

Allium sativum (garlic) suppresses leukocyte inflammatory cytokine production in vitro: Potential therapeutic use in the treatment of inflammatory bowel disease

2002

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BackgroundCytokines involved in inflammatory bowel disease (IBD) direct a predominantly cell‐mediated T‐ helper‐1 (Th1) immune response. The nonspecific anti‐inflammatory treatment being used in the management of patients with IBD has not changed much since the 1970s and new therapeutic agents are keenly sought. Several compounds isolated from Allium sativum (garlic) modulate leukocyte cell proliferation and cytokine production.MethodsTo investigate the possible therapeutic effects of garlic in the treatment of patients with IBD, whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated in the presence of various concentrations of garlic extract and the effect on leukocyte cytokine production was determined in vitro using multiparameter flow cytometry.ResultsMonocyte interleukin (IL)‐12 production was inhibited significantly in the presence of low concentrations of garlic extract (≥0.1 μg/ml total protein). Monocyte IL‐10 production increased significantly and monocyte tumor necrosis factor‐alpha (TNF‐α), IL‐1α, IL‐6, IL‐8, T‐cell interferon‐gamma (IFN‐γ), IL‐2, and TNF‐α decreased significantly in the presence of ≥10 μg/ml garlic extract. Twenty to fifty percent of the immunomodulatory activity of garlic extract on cytokine production was acid labile. The inhibitory activity of methylprednisolone, a commonly used anti‐inflammatory in IBD, with garlic on leukocyte cytokine production was additive.ConclusionsBy inhibiting Th1 and inflammatory cytokines while upregulating IL‐10 production, treatment with garlic extract may help to resolve inflammation associated with IBD. An in vivo animal model study needs to be undertaken to determine the significance of these in vitro findings. Cytometry 48:209–215, 2002. © 2002 Wiley‐Liss, Inc.

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“…Recent studies demonstrate the presence of HOCl-modified proteins in inflammatory bowel disease (9) and in atherosclerotic plaques (10). HOCl is cell permeable and reacts readily with thiols, thioethers and amino groups (11,12).…”

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confidence: 99%

Myeloperoxidase-derived Hypochlorous Acid Antagonizes the Oxidative Stress-mediated Activation of Iron Regulatory Protein 1

Mütze

Hebling

Stremmel

et al. 2003

Journal of Biological Chemistry

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Hypochlorous acid (HOCl) is a highly reactive product generated by the myeloperoxidase reaction during the oxidative burst of activated neutrophils, which is implicated in many bactericidal and cytotoxic responses. Recent evidence suggests that HOCl may also play a role in the modulation of redox sensitive signaling pathways. The short half-life of HOCl and the requirement for a continuous presence of H 2 O 2 as a substrate for its myeloperoxidase-catalyzed generation make the study of HOCl-mediated responses very difficult. We describe here an enzymatic model consisting of glucose/glucose oxidase, catalase, and myeloperoxidase (GOX/CAT/ MPO) that allows the controlled generation of both HOCl and H 2 O 2 and thus, mimics the oxidative burst of activated neutrophils. By employing this model we show that HOCl prevents the H 2 O 2 -mediated activation of iron regulatory protein 1 (IRP1), a central post-transcriptional regulator of mammalian iron metabolism. Activated IRP1 binds to "iron-responsive elements" (IREs) within the mRNAs encoding proteins of iron metabolism and thereby controls their translation or stability. The inhibitory effect of HOCl is not a result of a direct modification of IRP1 by this oxidant. Kinetics experiments provide evidence that HOCl intervenes with the signaling cascade, which results in the activation of IRP1. We further demonstrate that HOCl antagonizes the H 2 O 2 -mediated increase in the levels of transferrin receptor, which is a downstream target of IRP1. Our findings suggest that HOCl can modulate signaling pathways in a concerted action with H 2 O 2 . The GOX/ CAT/MPO system provides a valuable tool for studying the regulatory function of HOCl.Phagocytic cells, including neutrophils and macrophages, have an important function in the inflammatory response. Upon stimulation, they undergo an "oxidative burst" resulting in the generation of large amounts of superoxide by a membrane associated NADPH oxidase, which is further metabolized to H 2 O 2 by either spontaneously or by superoxide dismutases (1). Hydrogen peroxide is mostly utilized by the heme enzyme myeloperoxidase (MPO) 1 that is released from azurophilic granules upon neutrophil activation. Being activated, myeloperoxidase is able to oxidize Cl Ϫ to hypochlorous acid (HOCl). Approximately up to 70% of H 2 O 2 is converted by myeloperoxidase (2) to hypochlorous acid (HOCl), a highly reactive species with potent microbicidal and cytotoxic properties (1). On the other hand, activated MPO oxidizes a wide variety of different substrates by abstracting only one electron under formation of radical products. These substrates include tyrosine, tryptophan, sulfhydryls, phenol, and indole derivatives, nitrite, hydrogen peroxide, xenobiotics, and others (3-5). Thus, myeloperoxidase produces several reactive oxidants by utilizing hydrogen peroxide.While the generation of HOCl is of fundamental significance for combating infection, sustained levels of this oxidant are associated with side effects of inflammation, such as cell injury an...

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Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease.

Cited by 320 publications

References 39 publications

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Allium sativum (garlic) suppresses leukocyte inflammatory cytokine production in vitro: Potential therapeutic use in the treatment of inflammatory bowel disease

Myeloperoxidase-derived Hypochlorous Acid Antagonizes the Oxidative Stress-mediated Activation of Iron Regulatory Protein 1

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