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Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II

Nature volume 378, pages 406409 (23 November 1995) | Download Citation

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Abstract

PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms1,2. COX-1 is thought to provide cytoprotective effects3, whereas COX-2 is both inducible and the major isoform of inflammatory cells4. Reduction of prostaglandin 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 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.

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Author notes

    • Joseph E. Dinchuk
    •  & Richard J. Focht

    The DuPont Merck Pharmaceutical Company, Glenolden,Pennsylvania 19036-2307, USA

    • Vicki M. Eng

    University Laboratory Animal Resources, University of Pennsylvania,Philadelphia, Pennsylvania 19104-6021, USA

Affiliations

  1. The DuPont Merck Pharmaceutical Company, Wilmington,Delaware 19880-0400, USA

    • Joseph E. Dinchuk
    • , Bruce D. Car
    • , Richard J. Focht
    • , Jennifer J. Johnston
    • , Bruce D. Jaffee
    • , Maryanne B. Covington
    • , Nancy R. Contel
    • , Vicki M. Eng
    • , Robert J. Collins
    • , Philip M. Czerniak
    • , Stewart A. Gorry
    •  & James M. Trzaskos

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https://doi.org/10.1038/378406a0

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