Partial Hepatectomy–Induced Regeneration Accelerates Reversion of Liver Fibrosis Involving Participation of Hepatic Stellate Cells

Abstract

Hepatic fibrosis underlies most types of chronic liver diseases and is characterized by excessive deposition of extracellular matrix (ECM), altered liver architecture, and impaired hepatocyte proliferation; however, the fibrotic liver can still regenerate after partial hepatectomy (PH). Therefore, the present study was aimed at addressing whether a PH-induced regeneration normalizes ECM turnover and the possible involvement of hepatic stellate cells (HSC) during resolution of a pre-established fibrosis. Male Wistar rats were rendered fibrotic by intraperitoneal administration of swine serum for 9 weeks and subjected afterwards to 70% PH or sham-operation. Histological and morphometric analyses were performed, and parameters indicative of cell proliferation, collagen synthesis and degradation, and activation of HSC were determined. Liver collagen content was reduced to 75% after PH in cirrhotic rats when compared with sham-operated cirrhotic rats. The regenerating fibrotic liver oxidized actively free proline and had diminished transcripts for alpha-1 (I) collagen mRNA, resulting in decreased collagen synthesis. PH also increased collagenase activity, accounted for by higher amounts of pro-MMP-9, MMP-2, and MMP-13, which largely coincided with a lower expression of TIMP-1 and TIMP-2. Therefore, an early decreased collagen synthesis, mild ECM degradation, and active liver regeneration were followed by higher collagenolysis and limited deposition of ECM, probably associated with increased mitochondrial activity. Activated HSC readily increased during liver fibrosis and remained activated after liver regeneration, even during fibrosis resolution. In conclusion, stimulation of liver regeneration through PH restores the balance in ECM synthesis/degradation, leading to ECM remodeling and to an almost complete resolution of liver fibrosis. As a response to the regenerative stimulus, activated HSC seem to play a controlling role on ECM remodeling during experimental cirrhosis in rats. Therefore, pharmacological approaches for the resolution of liver fibrosis by blocking HSC activation should also evaluate possible effects on liver cell proliferation.