Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury

✍ Scribed by Yuko Ishida; Toshikazu Kondo; Akihiko Kimura; Kouichi Tsuneyama; Tatsunori Takayasu; Naofumi Mukaida

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 501 KB
• Volume: 36
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/eji.200535261

✦ Synopsis

Abstract

Neutrophils and macrophages infiltrate after acetaminophen (APAP)‐induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG‐treated wild‐type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)‐1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP‐induced liver injury, while HO‐1 was mainly expressed by macrophages. All anti‐granulocyte antibody‐treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)‐deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAP‐induced liver injury. However, APAP caused more exaggerated liver injury in CXCR2‐deficient mice with reduced macrophage infiltration and HO‐1 gene expression, compared with neutropenic WT mice. An HO‐1 inhibitor, tin‐protoporphyrin‐IX, significantly increased APAP‐induced mortality, implicating HO‐1 as a protective molecule for APAP‐induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS‐expressing neutrophils and HO‐1‐expressing macrophages, and the balance between these two molecules may determine the outcome of APAP‐induced liver injury.