Human colonocyte detoxification

Roediger, W. E. W.; Babidge, Wendy

doi:10.1136/gut.41.6.731

Cited by 56 publications

(32 citation statements)

References 77 publications

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“…Genetic defects in intestinal goblet cells can lead to spontaneous inflammation (33). In addition to mucosal barrier defense, the GI tract also secretes immunologically active substances that modulate mucosal inflammatory and immune responses (41).…”

Section: Discussionmentioning

confidence: 99%

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Liu

Patel

Walter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 304: G793-G803, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00249.2012.-Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)-and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSSand S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc. inflammation; dextran sodium sulfate; transgenic mice; IL-8 INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease that affects the entire gastrointestinal (GI) tract and the colonic mucosa and is associated with an increased risk for colon cancer. IBD is characterized by relapses (acute flare) and remissions, which are related to genetic basis and involve immune-mediated tissue injury followed by repair. Recent studies have shown that cytokines play a key role in regulating IBD (9, 40). There is increased incidence of IBD in urban areas of industrialized nations (29,42). Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes with proteolytic activity against extracellular matrix (ECM) proteins and are also known to play an important role for normal tissue remodeling (47). MMPs have also been shown to be involved in several pathological conditions such as IBD, tumor invasion, and colorect...

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Section: Discussionmentioning

confidence: 99%

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Liu

Patel

Walter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Detoxification enzyme depletion may be an important factor in the initiation and progression of UC [44]. Cellular transporters, such as ABCB1, multidrug resistance (MDR)1, and ABCC1-3 (MRP1-3), maintain IEC health by extruding drugs, nutrients, or bacterial compounds into the gut lumen [45,46].…”

Section: Abnormal Detoxification Pathwaysmentioning

confidence: 99%

Clinical implications of oxidative stress and antioxidant therapy

Dryden

Deaciuc²,

Arteel³

et al. 2005

Curr Gastroenterol Rep

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Oxidative stress occurs when there is an imbalance between generation of reactive oxygen species and inadequate antioxidant defense systems. Oxidative stress can cause cell damage either directly or through altering signaling pathways. Oxidative stress is a unifying mechanism of injury in many types of disease processes, including gastrointestinal diseases. For example, in alcoholic liver disease, reactive oxygen species have been detected through direct spin-trapping techniques and through indirect markers, such as products of lipid peroxidation. A host of antioxidants have protected against liver injury in animal models of alcoholic liver disease. Similarly, in inflammatory bowel disease, oxidative stress has been postulated to play a role in disease initiation and progression, and antioxidant therapy, such as green tea polyphenols and gene therapy with superoxide dismutase, has a markedly attenuated disease. Downregulation of specific detoxification genes may play a role in the pathogenesis of inflammatory bowel disease, especially in ulcerative colitis. Oxidative stress is postulated to play a sustaining role in acute and chronic pancreatitis. Antioxidant supplementation has been used with some success in the treatment of chronic pancreatitis. This review covers recent findings related to oxidative stress in liver disease, inflammatory bowel disease, and pancreatitis.

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“…Disturbance of the integrity of the epithelial cell barrier contributes to the development of mucosal inflammation exposing the intestinal immune system to bacteria products and toxins [12]. Protective mechanisms that maintain intestinal barrier function include detoxification and biotransformation of luminal substances.…”

Section: Rifaximin Regulates the Expression Of Detoxification Genes Imentioning

confidence: 99%

“…In the last decade results from animal models as well as studies of IBD patients have shown that colonic epithelial cells might become unable to detoxify toxic metabolites in inflammation [6][7][8][9][10][11]. Despite the pathogenesis of this epithelial dysfunction is multifactorial and somewhat elusive, the concept of a multilevel alteration of the intestinal detoxification system is recognized as pathogenetic mechanism in IBD [6,12].…”

Section: Introductionmentioning

confidence: 99%