Low doses of Celecoxib attenuate gut barrier failure during experimental peritonitis

Scott S. Short, Jin Wang, Shannon L. Castle, G. Esteban Fernandez, Nancy Smiley, Michael Zobel, Elizabeth M. Pontarelli, Stephanie C. Papillon, Anatoly V. Grishin, Henri R. Ford

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The intestinal barrier becomes compromised during systemic inflammation, leading to the 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 (TJ)-associated proteins junction-associated molecule-A and zonula occludens-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 TJs. 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.

Original languageEnglish (US)
Pages (from-to)1265-1275
Number of pages11
JournalLaboratory Investigation
Volume93
Issue number12
DOIs
StatePublished - Dec 2013

Keywords

  • Celecoxib
  • cyclooxygenase-2
  • gut barrier failure
  • gut origin sepsis
  • peritonitis
  • prostaglandin E2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Short, S. S., Wang, J., Castle, S. L., Fernandez, G. E., Smiley, N., Zobel, M., Pontarelli, E. M., Papillon, S. C., Grishin, A. V., & Ford, H. R. (2013). Low doses of Celecoxib attenuate gut barrier failure during experimental peritonitis. Laboratory Investigation, 93(12), 1265-1275. https://doi.org/10.1038/labinvest.2013.119