Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury.
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.
Division of Molecular Bioregulation, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
Yuko
Y
Ishida
Toshikazu
T
Kondo
Akihiko
A
Kimura
Kouichi
K
Tsuneyama
Tatsunori
T
Takayasu
Naofumi
N
Mukaida
D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000187:drug effects; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000187:drug effects; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018712:Analgesics, Non-Narcotic; D023063:Receptors, Interleukin-8B; D000082:Acetaminophen; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1