Damage of the non parenchymal cells after acetaminophen intoxication is critical for liver regeneration

Acetaminophen (APAP)is a safe antipyretic and pain relieving drug when used at normal therapeutic doses. However, overdoses of APAP are commonly associated with acute liver damage. Due to the vital functions of the liver, a rapid well-orchestrated regeneration is essential after injury, in contrast to the quiescent state of healthy liver. The aim of this study is to investigate the influence of APAP intoxication on various hepatic cells in mice and the impact of each individual cell type on liver regeneration. For this purpose male C57B6/n mice received a single low (200 mg/kg) or high (450 mg/kg) dose of APAP. Blood as well as liver tissue samples were collected in a time resolved manner after APAP injection. Histopathological analysis revealed pericentral liver damage after intoxication with 200 mg/kg. In addition to the centrilobular damage, a wide spread haemorrhage was observed after injection of 450 mg/kg. Moreover, in contrast to the complete regeneration of the dead cell area by day four after intoxication with 200 mg/kg, delayed liver regeneration was observed following intoxication with high doses of acetaminophen. Alpha-smooth muscle actin staining, a marker of activate stellate cells, showed a strong positive signal started as early as day one after injection of 200 mg/kg. In contrast, a very weak and delayed signal of alpha-smooth muscle actin, started after day three, was observed following injection of high doses of APAP. Moreover, the sinusoidal endothelial cells were highly compromised after injection of high doses of APAP as assessed by CD31 staining. In order to prove the critical role of the non parenchymal cells in liver regeneration, a defined region of the liver lobule was burned by laser using two-photon microscope. The laser was adjusted to target only hepatocytes or hepatocytes plus the non parenchymal cells in this region. Killing of only hepatocytes resulted in full recovery within six days. In contrast, after damage of the non parenchymal cells collagen deposition was observed in the dead cell area.

In summary, the results revealed that loss of hepatocytes is not critical for liver regeneration. In contrast, damage of the non parenchymal cells might leads to the switch from regenerative to fibrotic signal.

Corresponding author: Ghallab, Ahmed

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