| Popis: |
Patients with cirrhosis characteristically develop haemodynamic changes which include increased cardiac output, decreased systemic vascular resistance and paradoxically, increased portal pressure. Studies to date largely in animal models, have suggested that a decrease in hepatic nitric oxide may be important. The studies described in this thesis provide evidence for significantly elevated portal pressure in alcoholic hepatitis patients, who were shown to have a marked additional inflammatory response on the background of cirrhosis, and a more severe expression of disease. Studies in patients and a galactosamine rodent model confirmed a decrease in endothelial nitric oxide synthase (NOS) activity in the context of inflammatory liver injury. Following on from these observations, further studies explored the role of potential regulators of NOS which may have accounted for its decrease in activity in liver disease. Studies of asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, showed that it was markedly increased in liver failure in both patients and in an animal model. The data suggested this may result from a decreased metabolism (through reduced expression of its metabolizing enzyme, dimethylarginine-dimethylaminohydrolase) or/and increased synthesis by protein arginine methyltransferases. ADMA was shown to correlate with severity of portal pressure, and with increased organ failure and death in decompensated cirrhosis, suggesting that it may have a potential use as a biomarker of disease severity. Other novel regulators of endothelial NOS were also explored including the recently described potential NOS inhibitor, NOSTRIN (nitric oxide synthase traffic inducer). It was demonstrated that NOSTRIN was up-regulated at both message and protein levels in liver disease patients and this was most marked in those with additional inflammation. A further novel observation was the identification of a variant of NOSTRIN which was only found in cirrhosis patients and not in normal liver tissue. The findings from these studies provide a better understanding of the importance of inflammation in the context of vascular dysfunction in cirrhosis and highlight some potential novel therapeutic targets. |
