Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration

Robert Langenbach; Scott G. Morham; Howard F. Tiano; Charles D. Loftin; Burhan I. Ghanayem; Patricia C. Chulada; Joel F. Mahler; Christopher A. Lee; Eugenia H. Goulding; Kimberly D. Kluckman; H. S. Kim; Oliver Smithies

doi:10.1016/0092-8674(95)90126-4

Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration

Robert Langenbach, Scott G. Morham, Howard F. Tiano, Charles D. Loftin, Burhan I. Ghanayem, Patricia C. Chulada, Joel F. Mahler, Christopher A. Lee, Eugenia H. Goulding, Kimberly D. Kluckman, H. S. Kim, Oliver Smithies

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

1063 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	483-492
Number of pages	10
Journal	Cell
Volume	83
Issue number	3
DOIs	https://doi.org/10.1016/0092-8674(95)90126-4
State	Published - Nov 3 1995

Bibliographical note

Funding Information:
Correspondence should be addressed to Ft. L. The authors are grateful to Dr. L. Marnett for his constructive comments on the manuscript and thank Drs. J. Krege and T. Eling for critically reading the manuscript. The authors thank Dr. D. Dewitt for supplying the antibody to COX-1. We appreciate the fine efforts of R. Ingram and the Comparative Medicine Branch for animal care, T. McIntyre for assistance in the NSAID studies, and 6. Gaul for the necropsy work, as well as the National Institute of Environmental Health Sciences histology laboratory for preparation of tissues. 0. S. is supported by National Institutes of Health grants GM20069 and HL49227. S. G. M. is an American Cancer Society fellow (#PF-3973).

Funding

Correspondence should be addressed to Ft. L. The authors are grateful to Dr. L. Marnett for his constructive comments on the manuscript and thank Drs. J. Krege and T. Eling for critically reading the manuscript. The authors thank Dr. D. Dewitt for supplying the antibody to COX-1. We appreciate the fine efforts of R. Ingram and the Comparative Medicine Branch for animal care, T. McIntyre for assistance in the NSAID studies, and 6. Gaul for the necropsy work, as well as the National Institute of Environmental Health Sciences histology laboratory for preparation of tissues. 0. S. is supported by National Institutes of Health grants GM20069 and HL49227. S. G. M. is an American Cancer Society fellow (#PF-3973).

Funders	Funder number
National Institutes of Health (NIH)	HL49227
National Institute of General Medical Sciences	R01GM020069

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Cite this

Langenbach, R., Morham, S. G., Tiano, H. F., Loftin, C. D., Ghanayem, B. I., Chulada, P. C., Mahler, J. F., Lee, C. A., Goulding, E. H., Kluckman, K. D., Kim, H. S., & Smithies, O. (1995). Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell, 83(3), 483-492. https://doi.org/10.1016/0092-8674(95)90126-4

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title = "Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration",

abstract = "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.",

author = "Robert Langenbach and Morham, {Scott G.} and Tiano, {Howard F.} and Loftin, {Charles D.} and Ghanayem, {Burhan I.} and Chulada, {Patricia C.} and Mahler, {Joel F.} and Lee, {Christopher A.} and Goulding, {Eugenia H.} and Kluckman, {Kimberly D.} and Kim, {H. S.} and Oliver Smithies",

note = "Funding Information: Correspondence should be addressed to Ft. L. The authors are grateful to Dr. L. Marnett for his constructive comments on the manuscript and thank Drs. J. Krege and T. Eling for critically reading the manuscript. The authors thank Dr. D. Dewitt for supplying the antibody to COX-1. We appreciate the fine efforts of R. Ingram and the Comparative Medicine Branch for animal care, T. McIntyre for assistance in the NSAID studies, and 6. Gaul for the necropsy work, as well as the National Institute of Environmental Health Sciences histology laboratory for preparation of tissues. 0. S. is supported by National Institutes of Health grants GM20069 and HL49227. S. G. M. is an American Cancer Society fellow (#PF-3973).",

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Langenbach, R, Morham, SG, Tiano, HF, Loftin, CD, Ghanayem, BI, Chulada, PC, Mahler, JF, Lee, CA, Goulding, EH, Kluckman, KD, Kim, HS & Smithies, O 1995, 'Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration', Cell, vol. 83, no. 3, pp. 483-492. https://doi.org/10.1016/0092-8674(95)90126-4

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AU - Ghanayem, Burhan I.

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N2 - 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.

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Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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