cPLA2 Is protective against COX inhibitor-induced intestinal damage

David C. Montrose, Krishna Kadaveru, Jillian N.M. Ilsley, Sierra H. Root, Thiruchanduri V. Rajan, Manish Ramesh, Frank C. Nichols, Bruce T. Liang, Dmitry Sonin, Arthur R. Hand, Simona Zarini, Robert C. Murphy, Glenn S. Belinsky, Masako Nakanishi, Daniel W. Rosenberg

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pansuppression of PG production via a genetic deletion of cPLA2 impacts the susceptibility to COX inhibitor-induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA2-/- and cPLA2+/+ littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA2-/- mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA2-/- mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA2-/- mice. Our data demonstrate that cPLA2 appears to be an important component in conferring protection against COX inhibitor-induced enteropathy, which may be mediated through affects on enterocytic mitochondria.

Original languageEnglish (US)
Pages (from-to)122-132
Number of pages11
JournalToxicological Sciences
Volume117
Issue number1
DOIs
StatePublished - Jun 18 2010

    Fingerprint

Keywords

  • COX inhibitor
  • Cytosolic phospholipase A
  • Intestine
  • Mitochondria

ASJC Scopus subject areas

  • Toxicology

Cite this

Montrose, D. C., Kadaveru, K., Ilsley, J. N. M., Root, S. H., Rajan, T. V., Ramesh, M., Nichols, F. C., Liang, B. T., Sonin, D., Hand, A. R., Zarini, S., Murphy, R. C., Belinsky, G. S., Nakanishi, M., & Rosenberg, D. W. (2010). cPLA2 Is protective against COX inhibitor-induced intestinal damage. Toxicological Sciences, 117(1), 122-132. https://doi.org/10.1093/toxsci/kfq184