Abcb4KO mice upon chemical intoxication represent features of acute-on-chronic liver failure in patients

Acute-on-chronic liver failure (ACLF) is a major complication in patients with chronic liver diseases. To better understand the pathophysiology and dynamics of ACLF, we developed a mouse model based on a two-hit hypothesis. The first hit is the deletion of Abcb4 in Balb/c mice, leading to liver fibrosis and ductular reaction similar to chronic hepatobiliary injury in patients. A sublethal dose (second hit) of CCl4 to 65 week-old Abcb4KO mice recapitulates an acute event in ACLF patients, similar to drug intoxication, binge drinking, or trauma. Livers and blood were collected at time points 0, 1, 2 and 4 d after the CCl4 injection. Histologically, massive hepatic necrosis is recorded at day 1 and 2 in mice with good prognosis after CCl4 treatment, whereas almost no necrosis is present in mice with poor prognosis at day 1 after CCl4 injection. A slight increase in Tunel positive cells (reflecting apoptosis) correlates with poor prognosis of mice. Better prognosis is additionally associated with less extrahepatic injury, i.e. kidney injury as indicated by a significant increase of serum creatinine concentrations. ACLF-assigned genes, i.e. IL6, Ccl5 and Crp are significantly induced in CCl4-exposed mice. In conclusion, a single administration of CCl4 to Abcb4KO mice recapitulates several features of ACLF patients, comprising a golden window of survival, advanced liver fibrosis, ductular reaction, massive hepatic necrosis and upregulation of ACLF-related genes. Therefore, the presented mouse model is promising to investigate ACLF pathomechanisms and possible therapeutic interventions.

Publication History

Article published online:
04 January 2021