PROSTAGLANDINS have wide-ranging effects in the body and are thought t
o be important mediators of inflammation. Cyclooxygenase (COX) plays a
keg regulatory role in prostaglandin synthesis, and occurs in both co
nstitutive (COX-1) and inducible (COX-2) isoforms(1,2). COX-1 is thoug
ht to provide cytoprotective effects(3), whereas COX-2 is both inducib
le and the major isoform of inflammatory cells(4), Reduction of prosta
glandin production by inhibition of cyclooxygenases appears to be the
main mechanism of action of most non-steroidal anti-inflammatory drugs
(NSAIDS)(5), Here we present an animal model of COX-2 deficiency that
was generated by gene targeting. Defects in null mice correlating wit
h reduced viability included renal alterations, characteristic of rena
l 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 mitig
ation of endotoxin-induced hepatocellular cytotoxicity was observed.