Platelets mediate neutrophil infiltration and exacerbate liver injury and sinusoidal endothelial cell damage after a severe acetaminophen overdose in mice

Abstract

Acetaminophen (APAP) overdose, the leading cause of acute liver failure in the US, is accompanied by hepatocyte necrosis and liver sinusoidal endothelial cell (LSEC) damage, with hepatic neutrophil infiltration and platelet deposition. However, the exact role played by platelets in the pathophysiology is not fully understood. To investigate this, we depleted platelets in C57Bl/6 J mice by injecting 2 mg/kg anti-CD41 antibody or IgG control 12 and 2 h before a moderate (300 mg/kg) or severe (600 mg/kg) APAP overdose. Platelet depletion did not affect liver injury as measured by plasma ALT levels and hepatic areas of necrosis 24 h after a moderate APAP overdose, but reduced hepatic neutrophil infiltration. After a severe overdose, platelet depletion caused a significant reduction in hepatic neutrophil infiltration, but contrary to the moderate overdose, it also significantly reduced liver injury. These findings were confirmed with a second platelet-depleting antibody (CD42b antibody). These results corroborate our previous findings, which showed that neutrophils exacerbate liver injury only after a severe APAP overdose but not a moderate one. Furthermore, severe APAP overdose induced LSEC injury 24 h after APAP, which was significantly reduced in platelet-depleted mice as measured by intrahepatic hemorrhage, increased hepatic von Willebrand factor deposition, and elevated plasma levels of hyaluronan. Thus, platelets contribute to endothelial cell injury and mediate neutrophil recruitment, which aggravates liver injury after a severe APAP overdose, underscoring the role of platelets in the pathophysiology.

Keywords: Acute liver failure; Drug hepatotoxicity; LSEC; Liver inflammation; Von Willebrand factor.