title: Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA).
abstract: Hepatic macrophages play crucial roles in hepatotoxicity. We investigated immunophenotypes of macrophages in liver injury induced in rats by thioacetamide (TAA; 300 mg/kg, intraperitoneal) after hepatic macrophage depletion; hepatic macrophages were depleted by liposomal clodronate (CLD; 10 ml/kg, i.v.) one day before TAA injection. Samples were obtained on post-TAA injection days 0, 1, 2, 3, 5, and 7. TAA injection induced coagulation necrosis of hepatocytes on days 1 through 3 and subsequent reparative fibrosis on days 5 and 7 in the centrilobular area, accompanied by increased numbers of M1 macrophages (expressing cluster of differentiation [CD]68 and major histocompatibility complex class II) and M2 macrophages (expressing CD163 and CD204) mainly on days 1 through 3. TAA + CLD treatment markedly decreased the numbers of M1 and M2 macrophages mainly on days 1 through 3; CD163(+) Kupffer cells were most sensitive to CLD depletion. In TAA + CLD-treated rats, interestingly, coagulation necrosis of hepatocytes was prolonged with more increased levels of hepatic enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) to TAA-treated rats; reparative fibrosis was incomplete and replaced by dystrophic calcification in the injured area, indicating the aggravated damage. Furthermore, in TAA + CLD-treated rats, inflammatory factors (monocyte chemoattractant protein [MCP]-1, interferon-γ, tumor necrosis factor-α, and interleukin-10) and fibrosis-related factors (transforming growth factor-β1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1) were decreased at messenger RNA levels, indicating abnormal macrophage functions. It was clearly demonstrated that hepatic macrophages have important roles in tissue damage and remodeling in hepatotoxicity.
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Hossain M
authors.initials: HM
authors.lastname: Golbar
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Kavindra K
authors.initials: KK
authors.lastname: Wijesundera
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bondoc
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Anusha H
authors.initials: AH
authors.lastname: Tennakoon
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan yamate@vet.osakafu-u.ac.jp.
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology* / Q000473:pathology*; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D058628:Myofibroblasts / Q000737:chemistry / Q000378:metabolism; D009336:Necrosis; D051381:Rats; D011916:Rats, Inbred F344; D013853:Thioacetamide / Q000633:toxicity*
chemical_list: D013853:Thioacetamide
keywords: clodronate; coagulation necrosis; fibrosis; liver; macrophage; thioacetamide