TY - JOUR
T1 - cPLA2 Is protective against COX inhibitor-induced intestinal damage
AU - Montrose, David C.
AU - Kadaveru, Krishna
AU - Ilsley, Jillian N.M.
AU - Root, Sierra H.
AU - Rajan, Thiruchanduri V.
AU - Ramesh, Manish
AU - Nichols, Frank C.
AU - Liang, Bruce T.
AU - Sonin, Dmitry
AU - Hand, Arthur R.
AU - Zarini, Simona
AU - Murphy, Robert C.
AU - Belinsky, Glenn S.
AU - Nakanishi, Masako
AU - Rosenberg, Daniel W.
PY - 2010/6/18
Y1 - 2010/6/18
N2 - 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.
AB - 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.
KW - COX inhibitor
KW - Cytosolic phospholipase A
KW - Intestine
KW - Mitochondria
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U2 - 10.1093/toxsci/kfq184
DO - 10.1093/toxsci/kfq184
M3 - Article
C2 - 20562220
AN - SCOPUS:77955886058
SN - 1096-6080
VL - 117
SP - 122
EP - 132
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -