cPLA2 is protective against COX inhibitor-induced intestinal damage.
Cytosolic phospholipase A(2) (cPLA(2)) 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 cPLA(2) 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 cPLA(2)(-/-) and cPLA(2)(+/+) littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA(2)(-/-) 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 cPLA(2)(-/-) mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA(2)(-/-) mice. Our data demonstrate that cPLA(2) appears to be an important component in conferring protection against COX inhibitor-induced enteropathy, which may be mediated through affects on enterocytic mitochondria.
Montrose
David C
DC
Center for Molecular Medicine and Colon Cancer Prevention Program, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. dam2040@med.cornell.edu
Kadaveru
Krishna
K
Ilsley
Jillian N M
JN
Root
Sierra H
SH
Rajan
Thiruchanduri V
TV
Ramesh
Manish
M
Nichols
Frank C
FC
Liang
Bruce T
BT
Sonin
Dmitry
D
Hand
Arthur R
AR
Zarini
Simona
S
Murphy
Robert C
RC
Belinsky
Glenn S
GS
Nakanishi
Masako
M
Rosenberg
Daniel W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D020869:Gene Expression Profiling; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000293:injuries / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity*
D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D054510:Phospholipases A2, Cytosolic; D000068579:Celecoxib