Roles of pro-angiogenic and anti-angiogenic factors as well as matrix metalloproteinases in healing of NSAID-induced small intestinal ulcers in rats

Gyenge, Melinda; Amagase, Kikuko; Kunimi, Shino; Matsuoka, Rie; Takeuchi, Koji

doi:10.1016/j.lfs.2013.07.021

Cited by 17 publications

(15 citation statements)

References 51 publications

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“…The majority of experimental studies on NSAID-enteropathy have used single, highdose indomethacin administration to induce mucosal damage. In these models, the injury pattern consists mainly of multiple, hemorrhagic lesions involving the full thickness of intestinal wall [48,49,50], a picture that differ greatly from the ones seen at enteroscopy or video capsule endoscopy in patients taking NSAIDs chronically [11,12,13]. Most importantly, these acute models of intestinal damage may be not suitable to evaluate the protective effect of poorly absorbed antibiotics, like rifaximin, which need at least 7-10 days to consistently affect intestinal bacterial load, composition and activity [51].…”

Section: Discussionmentioning

confidence: 99%

Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic

Fornai

Antonioli

Pellegrini

et al. 2016

Pharmacological Research

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Nonsteroidal anti-inflammatory drugs, besides exerting detrimental effects on the upper digestive tract, can also damage the small and large intestine. Although the underlying mechanisms remain unclear, there is evidence that enteric bacteria play a pivotal role. The present study examined the enteroprotective effects of a delayed-release formulation of rifaximin-EIR (R-EIR, 50mg/kg BID, i.g.), a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, in a rat model of enteropathy induced by indomethacin (IND, 1.5mg/kg BID for 14 days) administration. R-EIR was administered starting 7 days before or in concomitance with IND administration. At the end of treatments, blood samples were collected to evaluate hemoglobin (Hb) concentration (as an index of digestive bleeding). Small intestine was processed for: (1) histological assessment of intestinal damage (percentage length of lesions over the total length examined); (2) assay of tissue myeloperoxidase (MPO) and TNF levels, as markers of inflammation; (3) assay of tissue malondialdehyde (MDA) and protein carbonyl concentrations, as an index of lipid and protein peroxidation, respectively; (4) evaluation of the major bacterial phyla. IND significantly decreased Hb levels, this effect being significantly blunted by R-EIR. IND also induced the occurrence of lesions in the jejunum and ileum. In both intestinal regions, R-EIR significantly reduced the percentage of lesions, as compared with rats receiving IND alone. Either the markers of inflammation and tissue peroxidation were significantly increased in jejunum and ileum from IND-treated rats. However, in rats treated with R-EIR, these parameters were not significantly different from those observed in controls. R-EIR was also able to counterbalance the increase in Proteobacteria and Firmicutes abundance induced by INDO. To summarize, R-EIR treatment significantly prevents IND-induced intestinal damage, this enteroprotective effect being associated with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.

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Section: Discussionmentioning

confidence: 99%

Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic

Fornai

Antonioli

Pellegrini

et al. 2016

Pharmacological Research

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“…MMP-9, an endopeptidase involved in wound healing through regulating the turnover of matrix proteins46, was also found decreased under these conditions. It is intriguing that MMP-9 was found to be increased during the healing of indomethacin-induced small intestinal damage in rats and that administration of MMP inhibitors significantly impaired the healing of ulceration during this treatment47. Serpina1, described as a potent blocker of hematopoietic stem cell mobilization48, was found to be increased in injured mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury

LePage

Bélanger

Jones

et al. 2016

Sci Rep

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The intestinal epithelial barrier is critical to limit potential harmful consequences from exposure to deleterious luminal contents on the organism. Although this barrier is functionally important along the entire gut, specific regional regulatory mechanisms involved in the maintenance of this barrier are poorly defined. Herein, we identified Gata4 as a crucial regulator of barrier integrity in the mouse proximal intestinal epithelium. Conditional deletion of Gata4 in the intestine led to a drastic increase in claudin-2 expression that was associated with an important increase of gut barrier permeability without causing overt spontaneous inflammation. Administration of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes enteritis, led to rapid and restricted proximal small intestinal injuries in Gata4 mutant mice as opposed to control mice. Comparative analysis of gene transcript profiles from indomethacin-challenged control and Gata4 mutant mice identified defects in epithelial cell survival, inflammatory cell recruitment and tissue repair mechanisms. Altogether, these observations identify Gata4 as a novel crucial regulator of the intestinal epithelial barrier and as a critical epithelial transcription factor implicated in the maintenance of proximal intestinal mucosal integrity after injury.

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“…Our results showed MMP-9 activity only after treatments with the vehicle and lansoprazole (7 days). Recent studies have highlighted the function of MMP-2 in the healing process of rat gastric ulcers induced by acetic acid (Gyenge et al, 2013), but the function of MMP-2 is not well understood. Our results also show that the seemingly healing macroscopic ulcer observed by treating animals with lansoprazole (7 days) may not represent a good wound healing because the presence of MMP-9 activity in gastric damage further demonstrates the persistence of the inflammatory process at the gastric mucosa.…”

Section: Discussionmentioning

confidence: 99%

Terminalia catappa L.: A medicinal plant from the Caribbean pharmacopeia with anti-Helicobacter pylori and antiulcer action in experimental rodent models

Silva

Angelis

Bonamin

et al. 2015

Journal of Ethnopharmacology

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Roles of pro-angiogenic and anti-angiogenic factors as well as matrix metalloproteinases in healing of NSAID-induced small intestinal ulcers in rats

Cited by 17 publications

References 51 publications

Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic

Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic

Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury

Terminalia catappa L.: A medicinal plant from the Caribbean pharmacopeia with anti-Helicobacter pylori and antiulcer action in experimental rodent models

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