Low doses of Celecoxib attenuate gut barrier failure during experimental peritonitis

Autor: Elizabeth M. Pontarelli, Stephanie Papillon, Henri R. Ford, G. Esteban Fernandez, Jin Wang, Shannon L. Castle, Michael J. Zobel, Scott S. Short, Anatoly Grishin, Nancy Smiley
Rok vydání: 2013
Předmět:
Zdroj: Laboratory investigation; a journal of technical methods and pathology
ISSN: 0023-6837
DOI: 10.1038/labinvest.2013.119
Popis: 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 E2 (PGE2) 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 PGE2 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 PGE2 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.
Databáze: OpenAIRE