Shear stress-induced nitric oxide release triggers the liver regeneration cascade

The trigger of the liver regeneration cascade is currently unknown and has been the subject of debate. We hypothesize that, following 2/3 partial hepa tectomy (PHX), an increase in the blood flow-to-liver mass ratio results in shear stress-induced nitric oxide (NO) release, which triggers the liver r egeneration cascade. Portal venous pressure (PVP), reflecting shear stress in the liver, increased to the same extent following PHX and selective port al vein branch ligation (PVL), a hemodynamic model of PHX, suggesting simil ar amounts of shear stress in both models. Two indices of the initiation of the liver regeneration cascade were used: proliferative factor (PF) activi ty in blood 4 h after PHX or PVL and hepatic c-fos mRNA expression 15 min. after PHX or PVL. PF activity and c-fos mRNA expression were increased to s imilar extents after PHX and PVL, suggesting a similar stimulus in both mod els. PF activity and c-fos mRNA expression were inhibited by administration of the nitric oxide synthase antagonist, L-NAME, and the NO donor, SIN-1, reversed the inhibition in both models. These results provide support for t he hypothesis that a hemodynamic change results in increased shear stress i n the liver causing generation of NO, which then triggers the liver regener ation cascade. (C) 2001 Academic Press.