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LIVER AND BILIARY TRACT

Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

¹Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; and ²Department of Surgery, University of Rochester, Rochester, New York

Submitted 9 January 2008 ; accepted in final form 20 August 2008

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI₂), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI₂ biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1^–/–, and COX-2^–/– mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI₂ biosynthesis were determined 1–7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI₂ biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1^–/– mice with NS398 or COX-2^–/– mice with SC560 restricted PGI₂ biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI₂ biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI₂ rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.

gene-deficient mice; portal vein ligation