M1/M2-macrophage Polarization-based Hepatotoxicity in d-galactosamine-induced Acute Liver Injury in Rats

• Published in: Toxicologic pathology 2018-10, Vol.46 (7), p.764-776
• Main Authors: Rahman, Nahid, Pervin, Munmun, Kuramochi, Mizuki, Karim, Mohammad R., Izawa, Takeshi, Kuwamura, Mitsuru, Yamate, Jyoji
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, Differentiation, Myelomonocytic - genetics; Apoptosis - drug effects; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - pathology; Cytokines - genetics; Galactosamine - toxicity; Liver - drug effects; Liver - immunology; Liver - pathology; Liver Function Tests; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages - drug effects; Macrophages - immunology; Macrophages - pathology; Male; Necrosis; Rats, Inbred F344; Receptors, Cell Surface - genetics
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623318801574

d-galactosamine (d-GalN) is a well-known hepatotoxic agent that causes liver injury. Conversely, hepatic macrophages play a crucial role in maintaining liver tissue integrity. Macrophage functions were investigated in hepatic lesions induced by a single intraperitoneal injection of d-GalN (800 mg/kg body weight [BW]) in 6-week-old F344 rats. Blood and liver samples were examined at 8 hr and on 1, 2, 3, and 5 days postsingle injection (PSI). Hepatic lesions consisting of degeneration/sporadic foci of coagulation necrosis, inflammatory cell reaction, and reparative fibrosis were seen on PSI days 1 and 2, reflected by significantly increased serum levels of aspartate transaminase and alanine transaminase and upregulation of CD68 M1 (tumor necrosis factor-α, interleukin [IL]-6, and interferon-γ) and CD163 M2 (transforming growth factor-β1, IL-10, monocyte chemoattractant protein-1, and IL-4) macrophage-related factors. Double immunofluorescence staining on PSI day 2 demonstrated that 82% of hepatic macrophages expressed of CD163/CD68 simultaneously; 65–75% of MHC class II macrophages showed co-expression of CD163 or CD68 and 95% CD204-expressing macrophages reacted to CD163 or CD68. These findings showed that both M1- and M2-macrophages contributed to the development of hepatic lesions induced by d-GalN and provided information about macrophage activation, indicating the importance of analysis of macrophage phenotypes for hepatotoxicity based on M1/M2-polarization.