Schulte Anthony, Groeneveld Dafna J, Wei Zimu, Hazel Bianca, Bernard Matthew P, Poole Lauren G, Luyendyk James P
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA.
Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
Res Pract Thromb Haemost. 2024 Jan 24;8(1):102323. doi: 10.1016/j.rpth.2024.102323. eCollection 2024 Jan.
Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure (ALF). Neutrophil activation has been associated with poor outcomes in patients with ALF and is proposed to amplify coagulation in this context. However, the precise role of neutrophils in APAP-induced liver injury is not known.
We used a dual antibody-mediated neutrophil depletion strategy to determine the role of neutrophils in mice challenged with different doses of APAP (300 or 600 mg/kg) that produce hepatotoxicity and ALF-like pathology.
Flow cytometry confirmed depletion of neutrophils in whole blood prior to APAP challenge. Mice given isotype control and challenged with 300 mg/kg APAP developed marked hepatocellular necrosis and showed an increase in biomarkers of coagulation cascade activation. Neutrophil depletion (anti-Ly6G) did not affect either liver injury or coagulation activation in mice challenged with 300 mg/kg APAP. Mice given isotype control and challenged with 600 mg/kg APAP developed hepatic necrosis alongside marked hemorrhage and congestion indicative of vascular injury. Interestingly, hepatic neutrophil and platelet accumulation were increased in mice given 600 mg/kg APAP compared with those given the lower APAP dose. Neutrophil depletion significantly reduced the severity of liver necrosis in mice challenged with 600 mg/kg APAP, without significantly impacting biomarkers of coagulation activity. Notably, neutrophil depletion significantly reduced hepatic platelet accumulation in mice challenged with 600 mg/kg APAP.
The results indicate a role of neutrophils in APAP-induced liver injury that is dependent on the APAP dose and suggest involvement of neutrophil-platelet interactions in promoting hepatic injury in experimental APAP-induced ALF.
对乙酰氨基酚（APAP）过量是药物性急性肝衰竭（ALF）的主要原因。中性粒细胞激活与ALF患者的不良预后相关，并被认为在这种情况下会放大凝血过程。然而，中性粒细胞在APAP诱导的肝损伤中的确切作用尚不清楚。
我们使用双抗体介导的中性粒细胞清除策略来确定中性粒细胞在接受不同剂量APAP（300或600mg/kg）攻击的小鼠中的作用，这些剂量会产生肝毒性和类似ALF的病理变化。
流式细胞术证实了在APAP攻击前全血中中性粒细胞的清除。给予同型对照并接受300mg/kg APAP攻击的小鼠出现明显的肝细胞坏死，并显示凝血级联激活的生物标志物增加。中性粒细胞清除（抗Ly6G）对接受300mg/kg APAP攻击的小鼠的肝损伤或凝血激活均无影响。给予同型对照并接受600mg/kg APAP攻击的小鼠出现肝坏死，同时伴有明显的出血和充血，提示血管损伤。有趣的是，与给予较低APAP剂量的小鼠相比，给予600mg/kg APAP的小鼠肝脏中性粒细胞和血小板积聚增加。中性粒细胞清除显著降低了接受600mg/kg APAP攻击的小鼠的肝坏死严重程度，而对凝血活性的生物标志物没有显著影响。值得注意的是，中性粒细胞清除显著减少了接受600mg/kg APAP攻击的小鼠肝脏中的血小板积聚。
结果表明中性粒细胞在APAP诱导的肝损伤中的作用取决于APAP剂量，并提示中性粒细胞-血小板相互作用参与了实验性APAP诱导的ALF中促进肝损伤的过程。
