Infiltrating neutrophils aggravate metabolic liver failure in fah-deficient mice
摘要：
Background&Aims:Mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase(fah~(-/-))was a useful animal model for studying liver failure.Tyrosine metabolic toxicants accumulate in hepatocytes over time infah~(-/-)mice,leading to hepatocyte necrosis which we propose release many type of damage associated molecular partems(DAMPs)and cause chronic inflammation.However,whether immune-mediated inflammations cause a second wave of liver damage infah~(-/-)mice have never been investigated.Methods:The progressive changes in body weight,survival rate and liver inflammation were examined after the protective drug(NTBC)withdrawal.Cell depletion and receptor blocking were used to define the key immune ceils and molecules in liver injury.Results:After removing ofNTBC,fah~(-/-)mice lost their body weight gradually,and finally died when the body weight largely reduced(low to 70%),along with increased serum ALT and total bilirubin.Importantly,a large amount of liverinfiltrating neutrophils were observed.Neutrophils depletion reduced the liver failure,and resulted in a better survival of fah-/-mice after NTBC withdrawal.The liver tissues produce more CCR2 chemokine,with neutrophils expressing more CCR2.CCR2 inhibition reduced the number of liver-infiltrating neutrophils and increased the expression of repair cytokine IL-22,with a longer survival offah~(-/-)mice after NTBC withdrawal.Conclusions:The excess infiltrating neutrophils exacerbate liver failure infah~(-/-)mice which can be attenuated by blocking CCR2.
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