An optimized peritonitis-induced ACLF model that reproduces the full spectrum of extrahepatic organ failures in mice.

BACKGROUND: Acute-on-chronic liver failure (ACLF), which develops in patients with acutely decompensated cirrhosis, is characterized by multiple extrahepatic organ failures leading to high short-term mortality. Although major advances in the understanding of ACLF have been accomplished in the last years, the understanding of driving mechanisms underlying ACLF is hindered by the lack of proper animal models that faithfully reproduce both the systemic hyperinflammatory response and the full spectra of extrahepatic organ failures present in this condition. METHODS: ACLF was induced by acute induction of polymicrobial peritonitis secondary to the ligation and puncture of the cecum (CLP) in mice with chronic carbon tetrachloride (CCl4)-induced cirrhosis. The study included three groups: CCl4+CLP (n=10) mice with cirrhosis which underwent CLP surgery; CCl4+sham mice (n=10) and control mice (n=10). RESULTS: As compared to CCl4+sham, CCl4+CLP mice had higher short-term mortality and exhibited more severe hypoalbuminemia and hyperbilirubinemia, significantly higher AST and GGT levels and higher liver inflammatory burden. CCl4+CLP mice also showed increased serum creatinine and BUN levels and up-regulated expression of Kim-1, Il-6 and Tnf in the kidney, lower oxygen saturation (SpO2), higher serum renin concentration, higher international normalized ratio (INR) and worse neurological behavior test scores than CCl4+sham and control mice. In addition, CCl4+CLP mice showed widespread bacterial tissue colonization and exhibited increased serum cytokine levels, which correlated with the intensity of organ impairments. CONCLUSION: The CCl4+CLP model reproduces the full spectra of extrahepatic organ impairments present in patients with ACLF and represents an optimized murine model to experimentally explore the pathophysiology of this disease as well as new therapeutic approaches.