Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration.
Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2.
Langenbach
R
R
Laboratory of Experimental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Morham
S G
SG
Tiano
H F
HF
Loftin
C D
CD
Ghanayem
B I
BI
Chulada
P C
PC
Mahler
J F
JF
Lee
C A
CA
Goulding
E H
EH
Kluckman
K D
KD
Kim
H S
HS
Smithies
O
O
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016718:Arachidonic Acid / Q000009:adverse effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D003001:Cloning, Molecular; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005756:Gastritis / Q000139:chemically induced / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics*; D006720:Homozygote; D007213:Indomethacin / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology; D010032:Otitis Externa / Q000139:chemically induced; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D010974:Platelet Aggregation / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000235:genetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin