Regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure

Abstract

After parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic, and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase would be reflected in the gene expression profiles in the liver remnant by using a global porcine cDNA microarray chip with ϳ23,000 genes represented. Six pig livers were resected with 62% (low portal pressure resection) and 75% (high portal pressure resection), resulting in a portal venous pressure increase from a baseline of 6.1-8.2 and 12 mmHg, respectively. By sampling consecutive biopsies from the liver remnants, we found differentially expressed genes in the high portal pressure resection group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the low portal pressure resection group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation, development, and protein metabolism. Also common to both groups was both up-and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion, and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. In conclusion, the genetic regenerative response in the liver remnant to varies according to the level of resection. microarray; shear stress; partial hepatectomy; regeneration AFTER PARENCHYMAL LOSS, the liver regenerates restoring normal mass and metabolic function. Since Higgins and Anderson (33) formalized the study of liver regeneration in 1931, most studies on liver regeneration have been conducted in a model of 70% partial hepatectomy (PHx) in rodents. After PHx, several proapoptotic [transforming growth factor (TGF)-␤ and Fas ligand] and promitotic factors [IL-1, IL-6, EGF, hepatocyte growth factor (HGF), and TNF-␣; Refs. 22, 72] are known to be important humoral factors regulating induction, propagation, and termination of liver regeneration. Knockout studies in mice have demonstrated impaired regeneration in mice receptor negative for promitotic mediators (12) and hepatomegaly in mice receptor negative for proapoptotic mediators (16). Many of these humoral factors are detectable several hours after PHx (Refs. 50, 53, 76). However, later studies (65) have shown that liver regeneration commences already after 15 min post-PHx (via the detection of c-fos mRNA expression), suggesting more immediate triggering events. There is evidence indicating that the increased portal pressure and flow per gram of remaining liver tissue and hence sinusoidal shear stress after PHx may be a primary stimulus (53,63,64). Endothelial shear stress results in the production of nitric oxide (NO; Refs....

Liver Regeneration in Surgical Animal Models – A Historical Perspective and Clinical Implications

“…Later, liver regeneration after PHx in rats was shown to be inhibited by the administration of the NO antagonist N G -nitro- L -arginine methyl ester, and restored by the NO donor 3-morpholinosydnonimine-1 [45,46]. This potential renaissance of the flow theory was challenged by Mortensen et al [47] in a porcine model of PHx and gene expression analysis. By increasing the degree of liver resection (and consequently the rise in portal pressure and flow per gram remaining liver tissue) they observed a switch of the genetic response in the liver remnant from one of primarily cell cycle propagation (after 62% PHx) to that of modulation of the intracellular redox status and the caspase cascade (after 75% PHx) [47].…”

“…This potential renaissance of the flow theory was challenged by Mortensen et al [47] in a porcine model of PHx and gene expression analysis. By increasing the degree of liver resection (and consequently the rise in portal pressure and flow per gram remaining liver tissue) they observed a switch of the genetic response in the liver remnant from one of primarily cell cycle propagation (after 62% PHx) to that of modulation of the intracellular redox status and the caspase cascade (after 75% PHx) [47]. The different genetic response was proposed to be either due to the differences in sinusoidal pressure/shear stress and flow per gram remaining tissue, or due to differences in the amount of portal hepatotrophic substances delivered to the remnant.…”

Studying Liver Regeneration by Means of Molecular Biology: How Far We Are in Interpreting the Findings?

“…Usually time course of expression alterations after the intervention is used as a criterion for creating clusters, subgroups of genes with similar expression patterns, which is based on assumption that common activation or suppression indicates functional relationships among transcripts. Much database searching necessarily follows when interpreting the findings (15,39,59,64). Extensive use of public data repositories and bioinformatic platforms fosters their rapid development.…”

Hagen-Poiseuille’s law: The link between cirrhosis, liver stiffness, portal hypertension and hepatic decompensation

“…In the presence of increased HVPG, resection is associated with the differential expression of genes associated with apoptosis, rather than regeneration [13] . Several explanations have been proposed.…”