Charles D. Loftin

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.

Cyclooxygenase knockout mice: Models for elucidating isoform-specific functions

The development of cyclooxygenase (COX) deficient mice has allowed investigation into the individual physiological roles of the COX-1 and COX-2 isoforms. In the following article, the phenotypes of the two Ptgs (genes coding for COX-1 and COX-2) knockouts are summarized, and recent studies to investigate the effects of COX deficiency on cancer susceptibility, inflammatory response, gastric ulceration, and female reproductive processes are discussed. Also, the development and potential uses of mice deficient in both COX isoforms and mice containing only a single copy of one isoform are discussed. Additionally, when the data permit, the effects of genetic ablation of COX activity are compared with those of pharmacological inhibition of COX activity by nonsteroidal anti-inflammatory drugs. The data suggest that prostaglandins derived via the individual COX isoforms have separate as well as common functions. However, for the maintenance of normal physiology, it appears that deficiency of COX-2 has more profound effects than deficiency of COX-1.

Cyclooxygenase‐deficient Mice: A Summary of Their Characteristics and Susceptibilities to Inflammation and Carcinogenesis

ABSTRACT Cyclooxygenase (COX)‐1‐ and COX‐2‐deficient mice have unique physiological differences that have allowed investigation into the individual biological roles of the COX isoforms. In the following, the phenotypes of the two COX knockout mice are summarized, and recent studies to investigate the effects of COX deficiency on inflammatory responses and cancer susceptibility are discussed. The data suggest that both isoforms have important roles in the maintenance of physiological homeostasis and that such designations as housekeeping and/or response gene may not be entirely accurate. Furthermore, data from COX‐deficient mice indicate that both isoforms can contribute to the inflammatory response and that both isoforms have significant roles in carcino‐genesis.

Phenotypes of the COX-deficient mice indicate physiological and pathophysiological roles for COX-1 and COX-2.

The development of mice deficient in either cyclooxygenase-1 (COX-1) or COX-2, as well as mice deficient in both COX isoforms, has provided models to elucidate the physiological and pathophysiological roles of these enzymes. The findings obtained with the COX-deficient mice suggest that COX-2 may be more important than COX-1 for supplying prostaglandins (PGs) to maintain tissue homeostasis. Furthermore, both isoforms may be involved in the development of diseases, such as inflammation and cancer. Therefore, the contribution of each isoform to the prevention or development of disease is more complex than originally described. Studies with the COX-deficient mice suggest that in addition to COX-2-selective inhibition, therapeutic advances may also be achieved with COX-1-selective inhibitors which lack gastrointestinal side effects.