Journal Article

cPLA<sub>2</sub> 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 and Daniel W. Rosenberg

in Toxicological Sciences

Volume 117, issue 1, pages 122-132
Published in print September 2010 | ISSN: 1096-6080
Published online June 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq184
cPLA2 Is Protective Against COX Inhibitor–Induced Intestinal Damage

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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 pan-suppression 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.

Keywords: cytosolic phospholipase A2; COX inhibitor; mitochondria; intestine

Journal Article.  7062 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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