Increased sinusoidal flow is not the primary stimulus to liver regeneration

Gene expression profiling from the shunted segments does not suggest that increased sinusoidal flow per se results in activation of genes promoting mitosis. Hyperperfusion over three weeks results in the whole liver gaining a supranormal weight of 3.9% of the total body weight (versus the normal 2.5%). Contrary to our hypothesis, the weight gain was observed on the non-shunted side without an increase in sinusoidal flow.An isolated increase in sinusoidal flow does not have the same genetic, microscopic or macroscopic impact on the liver as that seen in the liver remnant after partial hepatectomy, indicating that increased sinusoidal flow may not be a sufficient stimulus in itself for the initiation of liver regeneration.Since Higgins and Anderson formalized the study of liver regeneration in 1931 [1] most studies have been conducted in a model of 70% partial hepatectomy (PHx) in rodents. Following PHx, several pro-mitotic (IL-1, IL-6, EGF, HGF, TNFα) and pro-apoptotic factors (TGFβ, Fas ligand) are known to be important substances regulating the initiation, propagation and termination of liver regeneration [2-5]. Many of these blood borne factors are detectable several hours after PHx [6-8], and constitute the basis for the well established "humoral theory" of liver regeneration.However, later studies have shown that liver regeneration commences already 15 minutes after PHx (via the detection of c-fos mRNA) suggesting more immediate triggering events [9]. Several studies indicate that the increased portal pressure and flow per gram remaining liver tissue and hence sinusoidal shear stress that occurs immediately following PHx may be a primary stimulus to regeneration [7,10,11]. Endothelial shear stress results in the production of Nitric Oxide (NO) in the liver [12,13] and several studies have illustrated that liver regeneration is inhibited by administration of the NO synthase antagonist NG-nitro-L-arginine methyl ester (L-NAME) and restored by the NO donor 3-morpho