The role of nitric oxide and prostaglandins in triggering and potentiation of the liver regeneration cascade

Liver regeneration has been studied for over 100 years, and yet the trigger of the liver regeneration cascade is unknown. It has been hypothesized that nitric oxide (NO), released secondary to an increase in shear stress in the liver, triggers the liver regeneration cascade. To further test this hypothesis, c-fos mRNA expression after partial hepatectomy (PHX) and left branch portal vein ligation (PVL), a model of liver hyperplasia with similar hemodynamic conditions as PHX, was used as an index of initiation of the liver regeneration cascade. c-Fos mRNA expression increased after PHX and PVL, and was inhibited by the NOS antagonist, L-NAME. The NO donor, SIN-1, reversed the inhibition. Also, the increase in c-fos expression after PVL was prevented by ligation of the superior mesenteric artery, thus causing a 2/3 decrease in portal venous blood flow. These results support the hypothesis that a hemodynamic change after PHX or PVL causes shear stress and NO release in the remaining liver, which triggers the liver regeneration cascade.;Prostaglandins (PGs) are released after PHX and in response to shear stress. It was hypothesized that NO and PGs are released in response to increased shear stress after PHX, and work together to trigger the liver regeneration cascade. NOS or COX inhibition prevented the increase in c-fos expression after PHX. This inhibition was reversed by the NO donors, SIN-1 or SNAP, and PGE2 or PGI2, suggesting that NO and PGs work together and cause the increase in c-fos mRNA expression after PHX, and that excess amounts of exogenous NO or PGs can compensate for the absence of the other.;SNAP, the phosphodiesterase V antagonist, Zaprinast (ZAP), PGI2 , and the combination of all three, potentiated c-fos mRNA expression after PHX. Also, liver weight restoration, which includes the entire regeneration cascade, was potentiated by ZAP, 6-keto-PGF1α, a stable metabolite of PGI2, and the combination of ZAP and 6-keto-PG1α , 48 hours after PHX. Thus, NO and PGs can potentiate the liver regeneration cascade, and represent potential therapeutic targets for patients undergoing liver resection.