Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II.
Prostaglandins have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms. COX-1 is thought to provide cytoprotective effects, whereas COX-2 is both inducible and the major isoform of inflammatory cells. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS). Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2-/- mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D018390:Gene Targeting; D006331:Heart Diseases / Q000201:enzymology / Q000235:genetics; D007247:Infertility, Female / Q000201:enzymology / Q000235:genetics; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology / Q000201:enzymology; D008099:Liver / Q000196:embryology / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases