Cargando…

Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis

The intestinal barrier becomes compromised during systemic inflammation, leading to entry of luminal bacteria into the host and gut origin sepsis. Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. In this study we examined the role of cyclooxyge...

Descripción completa

Detalles Bibliográficos
Autores principales: Short, Scott S., Wang, Jin, Castle, Shannon L., Fernandez, G. Esteban, Smiley, Nancy, Zobel, Michael, Pontarelli, Elizabeth M., Papillon, Stephanie C., Grishin, Anatoly V., Ford, Henri R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966546/
https://www.ncbi.nlm.nih.gov/pubmed/24126890
http://dx.doi.org/10.1038/labinvest.2013.119
_version_ 1782308927171461120
author Short, Scott S.
Wang, Jin
Castle, Shannon L.
Fernandez, G. Esteban
Smiley, Nancy
Zobel, Michael
Pontarelli, Elizabeth M.
Papillon, Stephanie C.
Grishin, Anatoly V.
Ford, Henri R.
author_facet Short, Scott S.
Wang, Jin
Castle, Shannon L.
Fernandez, G. Esteban
Smiley, Nancy
Zobel, Michael
Pontarelli, Elizabeth M.
Papillon, Stephanie C.
Grishin, Anatoly V.
Ford, Henri R.
author_sort Short, Scott S.
collection PubMed
description The intestinal barrier becomes compromised during systemic inflammation, leading to entry of luminal bacteria into the host and gut origin sepsis. Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. In this study we examined the role of cyclooxygenase-2 (COX-2), a key enzyme in the production of inflammatory prostanoids, in gut barrier failure during experimental peritonitis in mice. I.p. injection of LPS or cecal ligation and puncture (CLP) increased the levels of COX-2 and its product prostaglandin E(2) (PGE(2)) in the ileal mucosa, caused pathologic sloughing of the intestinal epithelium, increased passage of FITC-dextran and bacterial translocation across the barrier, and increased internalization of the tight junction-associated proteins JAM-A and ZO-1. Luminal instillation of PGE(2) in an isolated ileal loop increased transepithelial passage of FITC-dextran. Low doses (0.5–1 mg/kg), but not a higher dose (5 mg/kg) of the specific COX-2 inhibitor Celecoxib partially ameliorated the inflammatory gut barrier failure. These results demonstrate that high levels of COX-2-derived PGE(2) seen in the mucosa during peritonitis contribute to gut barrier failure, presumably by compromising tight junctions. Low doses of specific COX-2 inhibitors may blunt this effect while preserving the homeostatic function of COX-2-derived prostanoids. Low doses of COX-2 inhibitors may find use as an adjunct barrier-protecting therapy in critically ill patients.
format Online
Article
Text
id pubmed-3966546
institution National Center for Biotechnology Information
language English
publishDate 2013
record_format MEDLINE/PubMed
spelling pubmed-39665462014-06-01 Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis Short, Scott S. Wang, Jin Castle, Shannon L. Fernandez, G. Esteban Smiley, Nancy Zobel, Michael Pontarelli, Elizabeth M. Papillon, Stephanie C. Grishin, Anatoly V. Ford, Henri R. Lab Invest Article The intestinal barrier becomes compromised during systemic inflammation, leading to entry of luminal bacteria into the host and gut origin sepsis. Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. In this study we examined the role of cyclooxygenase-2 (COX-2), a key enzyme in the production of inflammatory prostanoids, in gut barrier failure during experimental peritonitis in mice. I.p. injection of LPS or cecal ligation and puncture (CLP) increased the levels of COX-2 and its product prostaglandin E(2) (PGE(2)) in the ileal mucosa, caused pathologic sloughing of the intestinal epithelium, increased passage of FITC-dextran and bacterial translocation across the barrier, and increased internalization of the tight junction-associated proteins JAM-A and ZO-1. Luminal instillation of PGE(2) in an isolated ileal loop increased transepithelial passage of FITC-dextran. Low doses (0.5–1 mg/kg), but not a higher dose (5 mg/kg) of the specific COX-2 inhibitor Celecoxib partially ameliorated the inflammatory gut barrier failure. These results demonstrate that high levels of COX-2-derived PGE(2) seen in the mucosa during peritonitis contribute to gut barrier failure, presumably by compromising tight junctions. Low doses of specific COX-2 inhibitors may blunt this effect while preserving the homeostatic function of COX-2-derived prostanoids. Low doses of COX-2 inhibitors may find use as an adjunct barrier-protecting therapy in critically ill patients. 2013-10-14 2013-12 /pmc/articles/PMC3966546/ /pubmed/24126890 http://dx.doi.org/10.1038/labinvest.2013.119 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Short, Scott S.
Wang, Jin
Castle, Shannon L.
Fernandez, G. Esteban
Smiley, Nancy
Zobel, Michael
Pontarelli, Elizabeth M.
Papillon, Stephanie C.
Grishin, Anatoly V.
Ford, Henri R.
Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title_full Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title_fullStr Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title_full_unstemmed Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title_short Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis
title_sort low doses of celecoxib attenuate gut barrier failure during experimental peritonitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966546/
https://www.ncbi.nlm.nih.gov/pubmed/24126890
http://dx.doi.org/10.1038/labinvest.2013.119
work_keys_str_mv AT shortscotts lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT wangjin lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT castleshannonl lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT fernandezgesteban lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT smileynancy lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT zobelmichael lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT pontarellielizabethm lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT papillonstephaniec lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT grishinanatolyv lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis
AT fordhenrir lowdosesofcelecoxibattenuategutbarrierfailureduringexperimentalperitonitis