Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury
Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury
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DOI：
10.1002/eji.200535261
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发表时间：
2006-04-01
影响因子：
5.4
通讯作者：
Mukaida, N
中科院分区：
文献类型：
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作者：
Ishida, Y;Kondo, T;Mukaida, N
对乙酰氨基酚(APAP)诱导的肝损伤开始发展，中性粒细胞和巨噬细胞渗入。然而，他们的确切角色仍然难以捉摸。在未经处理和对照组的野生型(WT)小鼠中，腹腔注射APAP(750 mg/kg)可引起肝损伤，包括小叶中心肝坏死和中性粒细胞和巨噬细胞的浸润，注射后48h内死亡率约为50%。APAP注射显著增强肝内诱导型一氧化氮合酶(NOS)和血红素氧合酶(HO)-1的基因表达。此外，中性粒细胞表达一氧化氮合酶，可能是APAP肝损伤的加重分子，而HO-1主要由巨噬细胞表达。所有抗粒细胞抗体处理的中性粒细胞减少的WT和大多数CXC趋化因子受体2(CXCR2)缺陷的小鼠在相同剂量的APAP中存活，中性粒细胞浸润和NOS表达减少，表明中性粒细胞在APAP诱导的肝损伤中的致病作用。然而，与中性粒细胞减少的WT小鼠相比，APAP导致CXCR2缺陷小鼠更严重的肝损伤，巨噬细胞浸润和HO-1基因表达减少。HO-1抑制剂锡原卟啉-IX显著增加APAP诱导的死亡率，暗示HO-1是APAP诱导的肝损伤的保护分子。因此，CXCR2可能同时调节表达NOS的中性粒细胞和表达HO-1的巨噬细胞的渗透，两者之间的平衡可能决定APAP诱导的肝损伤的转归。
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 (NOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed NOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All antigranulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2) -deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and NOS 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 NOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury.