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Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiated into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. Aim: The aim of the present study was to investigate plasma levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) as proinflammatory and profibrogenic cytokines in cirrhotic rats and relate them with the level of plasminogen activator inhibitor-1(PAI1) as a marker of fibrinolytic activity. In addition, these cytokines were correlated with hepatic nitric oxide synthase activity (NOS). Subjects and methods: The study included 31 cirrhotic rats and 10 healthy controls. Induction of cirrhosis; Hepatic injury and fibrosis were done in rats by intraperitoneal injection (IP) of dimethylnitrosamine.(DMN). That were divided into 5 groups. Group I: as a control, group II were 8 cirrhotic rats, while group III were 7 cirrhotic ones with ascites. Group IV and V (n=8 rats) were cirrhotic rats injected with Ng nitro L-arginine methylester (L-NAME). Group V were ascitic in addition. Plasma TNF-α, IL-6 and PAI-1 and nitric oxide (NO) metabolites were measured. Hepatic nitrite level and NOS activity were also estimated. Results: Plasma TNF-α was significantly increased in all studied groups compared to control group. Plasma IL-6 was significantly higher in cirrhotic group with ascites and L-NAME administered groups compared to control one. Levels of plasma IL-6 were increased progressively with evolution of the disease. There was no statistically significant difference in plasma levels of PAI-1 between cirrhotic rats and control group, whereas, it was significantly increased in cirrhotic group with ascites upon L-NAME administration compared to control group. NOS activity is positively correlated with hepatic nitrite level. A positive significant correlation, also, existed between plasma TNF-α, IL-6 and NOS activity and hepatic nitrite in cirrhotic rats. Conclusion: The present study revealed that in cirrhotic rats; plasma levels of TNF-α and IL-6 were significantly elevated, and the elevation was more with progression of fibrosis. Plasma PAI-1 was increased in severe fibrotic liver with other injury. It could be suggested that the profibrogenic cytokines TNF-α and IL-6 are implicated in fibrogenesis in cirrhotic rats and are correlated with NOS activity which functions as an adaptive mechanism. They could be used clinically as indicators for occurrence and progression of fibrosis.

Levels of some plasma fibrotic factors and hepatic nitric oxide synthase in experimentally induced cirrhotic rats