COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice

Sigthorsson, G; Simpson, Robert J.; Walley, Matthew; Anthony, A; Foster, Russell G.; Hotz-Behoftsitz, Christoph; Palizban, Abbas Ali; Pombo, Joaquim; Watts, Jo; Morham, Scott G.; Bjarnason, Ingvar

doi:10.1053/gast.2002.33647

Cited by 181 publications

(182 citation statements)

References 54 publications

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“…High levels of intestinal COX-2 are reported in animal models of NEC, suggesting its pathogenic effects during intestinal inflammation (6,17). Conversely, administration of a COX-2 inhibitor results in a higher degree of intestinal inflammation in the rat NEC model (17), and studies with COX-2 knockout mice describe increased intestinal damage compared with wildtype controls (40). There have been only a few studies exploring the effect of different probiotics on COX-2 expression in intestinal cells or rat models of colitis.…”

Section: Discussionmentioning

confidence: 99%

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Khailová

Patrick

Arganbright

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

132

100

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Necrotizing enterocolitis (NEC) is a devastating intestinal disease of neonates, and clinical studies suggest the beneficial effect of probiotics in NEC prevention. Recently, we have shown that administration of Bifidobacterium bifidum protects against NEC in a rat model. Intestinal apoptosis can be suppressed by activation of cyclooxygenase-2 (COX-2) and increased production of prostaglandin E2 (PGE2). The present study investigates the effect of B. bifidum on intestinal apoptosis in the rat NEC model and in an intestinal epithelial cell line (IEC-6), as a mechanism of protection against mucosal injury. Premature rats were divided into the following three groups: dam fed, hand fed with formula (NEC), or hand fed with formula supplemented with B. bifidum (NEC + B. bifidum ). Intestinal Toll-like receptor-2 (TLR-2), COX-2, PGE2, and apoptotic regulators were measured. The effect of B. bifidum was verified in IEC-6 cells using a model of cytokine-induced apoptosis. Administration of B. bifidum increased expression of TLR-2, COX-2, and PGE2 and significantly reduced apoptosis in the intestinal epithelium of both in vivo and in vitro models. The Bax-to-Bcl-w ratio was shifted toward cell survival, and the number of cleaved caspase-3 positive cells was markedly decreased in B. bifidum -treated rats. Experiments in IEC-6 cells showed anti-apoptotic effect of B. bifidum . Inhibition of COX-2 signaling blocked the protective effect of B. bifidum treatment in both in vivo and in vitro models. In conclusion, oral administration of B. bifidum activates TLR-2 in the intestinal epithelium. B. bifidum increases expression of COX-2, which leads to higher production of PGE2 in the ileum and protects against intestinal apoptosis associated with NEC. This study indicates the ability of B. bifidum to downregulate apoptosis in the rat NEC model and in IEC-6 cells by a COX-2-dependent matter and suggests a molecular mechanism by which this probiotic reduces mucosal injury and preserves intestinal integrity.

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Section: Discussionmentioning

confidence: 99%

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Khailová

Patrick

Arganbright

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

132

100

View full text Add to dashboard Cite

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“…For instance, administration of selective COX-2 inhibitors to IL-10 Ϫ/Ϫ mice that develop spontaneous colitis, in which TNF levels are elevated (6) and demonstrably critical to the progression of the colitis (56), augmented the severity of colitis (25). More specifically, a recent study investigating the respective roles of COX-1 and COX-2 in the course of disease in a dextran sulfate sodium model of colitis demonstrated that COX-2 was critical for protection against ulceration in a later stage of disease (60).…”

Section: Discussionmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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“…A Unique Role for COX-2 in Intestinal Mucosa Integrity Is Identified Using COX-1 Ͼ COX-2 Mice-COX-1-deficient mice did not show any intestinal pathology with less than 3% PGE 2 synthesis in intestinal tissue (5,47) and were even more resistant to indomethacin-induced intestinal damage (5) than WT controls, whereas COX-2 deficiency caused intestinal ulceration and perforation resulting in peritonitis despite normal intestinal PGE 2 levels (10, 47). Long term administration of a COX-2 inhibitor caused identical intestinal lesions with increased fecal granulocyte marker protein (GMP), a gastrointestinal inflammation marker (47).…”

Section: Discussionmentioning

confidence: 99%

Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

Fan

Hui

et al. 2007

Journal of Biological Chemistry

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The prostaglandin G/H synthase enzymes, commonly termed COX-1 and COX-2, differ markedly in their responses to regulatory stimuli and their tissue expression patterns. COX-1 is the dominant source of "housekeeping" prostaglandins, whereas COX-2 synthesizes prostaglandins of relevance to pain, inflammation, and mitogenesis. Despite these distinctions, the two enzymes are remarkably conserved, and their subcellular distributions overlap considerably. To address the functional interchangeability of the two isozymes, mice in which COX-1 is expressed under COX-2 regulatory elements were created by a gene targeting "knock-in" strategy. In macrophages from these mice, COX-1 was shown to be lipopolysaccharide-inducible in a manner analogous to COX-2 in wild-type macrophages. However, COX-1 failed to substitute effectively for COX-2 in lipopolysaccharide-induced prostaglandin E 2 synthesis at low concentrations of substrate and in the metabolism of the endocannabinoid 2-arachidonylglycerol. The marked depression of the major urinary metabolite of prostacyclin in COX-2 null mice was only partially rescued by COX-1 knock-in, whereas the main urinary metabolite of prostaglandin E 2 was rescued totally. Replacement with COX-1 partially rescued the impact of COX-2 deletion on reproductive function. The renal pathology consequent to COX-2 deletion was delayed but not prevented, whereas the corresponding peritonitis was unaltered. Insertion of COX-1 under the regulatory sequences that drive COX-2 expression indicated that COX-1 can substitute for some COX-2 actions and rescue only some of the consequences of gene disruption. Manipulation of COX-2 also revealed a preference for coupling with distinct downstream prostaglandin synthases in vivo. These mice will provide a valuable reagent with which to elucidate the distinct roles of the COX enzymes in mammalian biology.

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COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice

Cited by 181 publications

References 54 publications

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

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