Colitis and colonic mucosal barrier dysfunction.

Gardiner, Keith; Anderson, Neil; Rowlands, B. J.; Barbul, Adrian

doi:10.1136/gut.37.4.530

Cited by 53 publications

(29 citation statements)

References 32 publications

(7 reference statements)

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“…31) Administration of ethanolic TNBS into the distal colon of rats initially produces acute colitis with massive granulocyte infiltration, epithelial destruction, and transmural necrosis. 31) As reported by Gardiner et al, 32) the severity of acute phase inflammation in TNBSinduced colitis is correlated with the degree of colonic permeability and the concentration of systemic endotoxin. Previously, we found that dietary HAS showed an inhibitory effect on endotoxin influx from the intestine in rats with hepatic injury induced by D-galactosamine administration, possibly through the promotion of IgA and mucin secretions into the lumen and stimulation of ileal mucosal proliferation.…”

Section: Discussionmentioning

confidence: 62%

Dietary Resistant Starch Alters the Characteristics of Colonic Mucosa and Exerts a Protective Effect on Trinitrobenzene Sulfonic Acid-induced Colitis in Rats

Morita¹,

Tanabe²,

Sugiyama³

et al. 2004

Bioscience, Biotechnology, and Biochemistry

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The protective effect of a dietary high-amylose cornstarch (HAS) against trinitrobenzene sulfonic acid (TNBS)-induced colitis was examined in rats. Rats were fed a HAS-free basal diet or, a 15% or 30% HAS supplemented diet for 10 d, and then received intracolonic TNBS to induce colitis and fed the respective diets for a further 8 d. HAS ingestion significantly protected colonic injuries as evidenced by lower colonic myeloperoxidase activity. Rats fed the HAS diet showed greater cecal short-chain fatty acid (SCFA) production than those fed the basal diet. Further, just before TNBS administration, HAS ingestion dose-dependently increased fecal and cecal mucin contents, and protein and nucleic acid contents in the colonic mucosa. HAS ingestion also reduced colonic permeability. The protective effect of HAS ingestion on TNBS-induced colitis is perhaps exerted through alterations in colonic mucosa, possibly due to cecal SCFA production.Key words: high-amylose cornstarch; trinitrobenzene sulfonic acid; short-chain fatty acids; mucin; ratsThe etiology of inflammatory bowel disease, encompassing Crohn's disease and ulcerative colitis, remains unknown, but studies in animal models suggest that disruption of mucosal barrier function may induce abnormal immune responses to luminal bacteria, resulting in acute and chronic inflammation in the large bowel.1) Mucosal barrier function has been ascribed to colonic epithelial cells based on mucus production and shedding of surface cells, which are replenished by renewal from crypt cells.2) In this regard, short-chain fatty acids (SCFA: mainly acetate, propionate, and butyrate), products of large bowel fermentation by bacteria, have been reported to be major fuels for colonic epithelial cells and to accelerate epithelial cell proliferation. 3,4) Earlier studies indicated that SCFA irrigation stimulated the mucosal repair process and decreased inflammation in human patients 5) and rats injected with trinitrobenzene sulfonic acid 6) (TNBS). Also, Barcelo et al. 7) found that a physiological concentration of butyrate and acetate caused a significant increase in mucus secretion in the lumen of isolated perfused rat colon. Greater mucin production might contribute to the lower incidence of bacterial translocation across the gut barrier reported in studies that fed dietary fiber. 8) Clearly, SCFAs are considered to be of benefit in the treatment of inflammatory bowel disease.Although SCFA delivery to the colon might be accomplished with an enteric-coated capsule or a rectal infusion of SCFA, the nutritional approach is more physiological, consistent, and cost-effective, and less stressful. One potential route is to increase the consumption of foods high in resistant starch, because studies in experimental animals have shown that the feeding of resistant starch, such as high-amylose cornstarch (HAS), increases the large bowel digesta SCFA level in rats [9][10][11] and pigs. 12) Previously we found that ingestion of HAS prevented endotoxin influx from the intestinal tract into the portal ...

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Section: Discussionmentioning

confidence: 62%

Dietary Resistant Starch Alters the Characteristics of Colonic Mucosa and Exerts a Protective Effect on Trinitrobenzene Sulfonic Acid-induced Colitis in Rats

Morita¹,

Tanabe²,

Sugiyama³

et al. 2004

Bioscience, Biotechnology, and Biochemistry

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“…Under conditions of chronic inflammation, epithelial ion transport function is reduced (Madara and Stafford, 1989;Gardiner et al, 1995). To determine whether the improvement in histological disease observed in the IL-10-deficient mice was associated with improvements in epithelial function, we examined ionic responsiveness of colonic tissue in Ussing chambers.…”

Section: Resultsmentioning

confidence: 99%

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

Popoff

Jijon

Monia

et al. 2002

J Pharmacol Exp Ther

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poly(ADP-ribose) polymerase-2 (PARP-2) is a newly described member of the PARP family of nuclear enzymes. Previous studies have shown pharmacological inhibition of PARP activity to have a beneficial role in attenuating inflammation. We developed a chemically modified 2Ј-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 110251) inhibitor of PARP-2 and tested it for efficacy in the interleukin (IL)-10-deficient mouse. In tissue culture, ISIS 110251 reduced PARP-2 mRNA expression in a concentration-and sequence-specific manner. In 129 Sv/Ev mice, ISIS 110251 reduced PARP-2 mRNA in liver by 80%. This reduction was dependent upon treatment duration and was independent of the method of delivery. In interleukin-10-deficient mice with established colitis, treatment with ISIS 110251 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitricoxide synthase activity, and attenuated inflammation. Our data demonstrate that selective inhibition of PARP-2 activity results in a marked improvement of colonic inflammatory disease in a mouse model of chronic colitis and a normalization of colonic function.

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“…Increased GI barrier permeability, in contrast, can lead to the penetration of normally excluded luminal substances into the mucosa and cause the initiation or continuation of inflammatory processes and mucosal damage (Hollander, 1998;Banan et al, 1999;Keshavarzian et al, 1999). Not surprisingly, loss of mucosal barrier integrity has been implicated in the pathogenesis of systemic and GI disorders, including inflammatory bowel disease (IBD) as well as trauma and burn-induced inflammation (Hollander, 1992;Gardiner et al, 1995;Unno et al, 1996Unno et al, , 1998Keshavarzian et al, 1999). For instance, loss of intestinal barrier permeability, which has been demonstrated in patients with IBD (Hollander, 1992;Gardiner et al, 1995Gardiner et al, , 1998, is now believed to be an integral factor in both the initiation and the perpetuation of the inflammatory cascade in IBD (Hollander, 1992(Hollander, , 1998Keshavarzian et al, 1992Keshavarzian et al, , 2003.…”

mentioning

confidence: 99%

“…Not surprisingly, loss of mucosal barrier integrity has been implicated in the pathogenesis of systemic and GI disorders, including inflammatory bowel disease (IBD) as well as trauma and burn-induced inflammation (Hollander, 1992;Gardiner et al, 1995;Unno et al, 1996Unno et al, , 1998Keshavarzian et al, 1999). For instance, loss of intestinal barrier permeability, which has been demonstrated in patients with IBD (Hollander, 1992;Gardiner et al, 1995Gardiner et al, , 1998, is now believed to be an integral factor in both the initiation and the perpetuation of the inflammatory cascade in IBD (Hollander, 1992(Hollander, , 1998Keshavarzian et al, 1992Keshavarzian et al, , 2003. The underlying difficulty in managing this inflammatory disorder is due to a lack of preventive strategies, which is in turn due to our limited understanding of the specific mechanisms responsi-ble for its pathophysiology.…”

mentioning

confidence: 99%

The δ-Isoform of Protein Kinase C Causes Inducible Nitric-Oxide Synthase and Nitric Oxide Up-Regulation: Key Mechanism for Oxidant-Induced Carbonylation, Nitration, and Disassembly of the Microtubule Cytoskeleton and Hyperpermeability of Barrier of Intestinal Epithelia

Banan¹,

Farhadi²,

Fields³

et al. 2003

J Pharmacol Exp Ther

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Using intestinal (Caco-2) cells, we found that oxidant-induced disruption of barrier integrity requires microtubule disassembly. Protein kinase C (PKC)-␦ isoform seems to be essential for disruption, but the mechanism is unknown. Because inducible nitric-oxide synthase (iNOS) is key to oxidant stress, we hypothesized that PKC-␦ activation is essential in oxidant-induced iNOS up-regulation and the consequent cytoskeletal oxidation and disarray and monolayer barrier dysfunction. Cells were transfected with an inducible plasmid to overexpress native PKC-␦ or with a dominant-negative to inhibit the activity of native PKC-␦. Clones were then incubated with oxidant (H 2 O 2 ) Ϯ modulators. Parental cells were treated similarly. Exposure to oxidant-disrupted monolayers by increasing native PKC-␦ activity, increasing six iNOS-related variables (iNOS activity and protein, nitric oxide, oxidative stress, tubulin oxidation and nitration), decreasing polymerized tubulin, disrupting the cytoarchitecture of microtubules, and causing monolayer dysfunction. Induction of PKC-␦ overexpression by itself (3.5-fold) led to oxidant-like disruptive effects, including activation of the iNOS-driven pathway. Overexpression-induced up-regulation of iNOS was potentiated by oxidants. iNOS inhibitors or oxidant scavengers were protective. Dominant inhibition of native PKC-␦ activity (99.5%) prevented all measures of oxidant-induced iNOS up-regulation and protected the monolayer barrier. The conclusions are as follows. 1) Oxidants induce loss of epithelial barrier integrity by oxidizing and disassembling the cytoskeleton, in part, through the activation of PKC-␦ and upregulation of iNOS. 2) Overexpression and activation of PKC-␦ are by themselves key for cellular injury by oxidative stress of iNOS. 3) We thus report a pathophysiological mechanism, activation of iNOS pathway and its injurious consequences to the cytoskeleton, including oxidation and nitration, among the "novel" subfamily of PKC isoforms.

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Colitis and colonic mucosal barrier dysfunction.

Cited by 53 publications

References 32 publications

Dietary Resistant Starch Alters the Characteristics of Colonic Mucosa and Exerts a Protective Effect on Trinitrobenzene Sulfonic Acid-induced Colitis in Rats

Dietary Resistant Starch Alters the Characteristics of Colonic Mucosa and Exerts a Protective Effect on Trinitrobenzene Sulfonic Acid-induced Colitis in Rats

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

The δ-Isoform of Protein Kinase C Causes Inducible Nitric-Oxide Synthase and Nitric Oxide Up-Regulation: Key Mechanism for Oxidant-Induced Carbonylation, Nitration, and Disassembly of the Microtubule Cytoskeleton and Hyperpermeability of Barrier of Intestinal Epithelia

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