title: The kinetics of damage-associated molecular patterns (DAMPs) and toll-like receptors during thioacetamide-induced acute liver injury in rats.
abstract: Drug-induced liver injury (DILI) is a common problem in human medicine and it is a major reason to withdraw marketed drugs. However, the mechanism of DILI is still less known. Damage-associated molecular patterns (DAMPs), such as high-mobility group boxes (HMGBs), S100 proteins and heat shock proteins (HSPs), are released from injured or necrotic cells, bind to toll-like receptors (TLRs) and modulate inflammatory reactions. Here we investigated the kinetics of DAMPs, TLRs and MHC class II in a rat model of DILI with thioacetamide (TAA). After TAA administration, extensive necrosis was observed on days 1 and 2, followed by infiltration of inflammatory cells on day 3. The levels of serum liver enzymes also peaked on day 1. Expression of HMGB-1, -2 and S100A4 peaked on day 2. TLR-4 was up-regulated on day 3. The number of MHC class II-positive macrophages increased until day 2. These results suggest that HMGB-1, -2 and S100A4 are associated with hepatocellular necrosis and that DAMPs may activate TLR-4 and MHC class II during TAA-induced liver injury. Our data would contribute to the elucidation of the mechanism of DILI.
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors: Mizuki
authors: M
authors: Kuramochi
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors: Takeshi
authors: T
authors: Izawa
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors: Munmun
authors: M
authors: Pervin
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors: Alexandra
authors: A
authors: Bondoc
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors: Mitsuru
authors: M
authors: Kuwamura
authors: Veterinary Pathology, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan. Electronic address: yamate@vet.osakafu-u.ac.jp.
authors: Jyoji
authors: J
authors: Yamate
mesh_terms: D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013853:Thioacetamide / Q000633:toxicity*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000067531:Alarmins; D000949:Histocompatibility Antigens Class II; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D013853:Thioacetamide
keywords: DAMPs; DILI; TLRs; Thioacetamide