부산대학교 도서관

Increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension, the main complication of cirrhosis. Architectural alterations of the liver parenchyma, but also a dynamic increase in the hepatic vascular tone contribute to the increased resistance to portal blood flow of cirrhotic livers. The increase in hepatic vascular tone is partly due to increased release of cyclooxygenase-1 (COX-1)-derived vasoconstrictive prostanoids and to a reduced bioavailability within the liver of the potent vasodilator nitric oxide (NO). Both mechanisms favouring the contraction of different elements within the cirrhotic liver. Indeed, activated hepatic stellate cells have been shown to contract or relax in response to vasoconstrictive prostanoids or NO respectively.Reduced NO bioavailability has been attributed to decreased endothelial nitric oxide synthase (eNOS) activity secondary to several disturbances in the posttranslational regulation of the enzyme.In several vascular disorders the potential of ROS to bind proteins, break DNA and promote cell damage by reacting with several cellular components has been involved in development of necrosis, inflammation, and apoptosis. In addition, an increase in the reactive oxygen specie superoxide (O2-), by rapidly reacting with NO, promotes a marked reduction in NO bioavailability followed by an increase in vascular tone.An increase in O2- levels due to increased production by xanthine oxidase (XO), NADPH oxidase or COX, among other enzymatic systems, and a reduced O2- scavenging by superoxide dismutase has been suggested to play a pathophysiological role in different liver disorders such as in alcoholic and non-alcoholic liver disease.Gene transfer of SOD has been shown to protect against oxidative stress and to improve endothelium-dependent relaxation in several situations, including myocardial infarction, liver transplantation, hypertension, diabetes , and aging. We hypothesize that in cirrhotic livers increased O2-, by reacting with NO, would contribute to reduce NO bioavailability. As a consequence, removing O2- from the cirrhotic livers could be a new therapeutic strategy to improve intrahepatic NO bioavailability, improve hepatic endothelial dysfunction and reduce portal pressure in rats with cirrhosis and portal hypertension.