PMID- 34954210 OWN - NLM STAT- MEDLINE DCOM- 20220429 LR - 20230302 IS - 1525-2191 (Electronic) IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 192 IP - 3 DP - 2022 Mar TI - Endotoxin-Stimulated Hepatic Stellate Cells Augment Acetaminophen-Induced Hepatocyte Injury. PG - 518-535 LID - S0002-9440(21)00529-0 [pii] LID - 10.1016/j.ajpath.2021.11.011 [doi] AB - Acetaminophen (APAP)-induced liver injury is influenced by inflammatory Gram-negative bacterial endotoxin [lipopolysaccharide (LPS)], mechanisms of which are not completely understood. Because LPS-stimulated perisinusoidal hepatic stellate cells (HSCs) produce cytokines that affect survival of hepatocytes, this study investigated their role in APAP-induced liver injury. Fed (nonstarved) rats were administered 5 mg/kg LPS or phosphate-buffered saline (PBS) vehicle, followed by 200 mg/kg APAP or PBS an hour later, and euthanized at 6 hours. Control rats received PBS at both time points. Both LPS and APAP caused mild hepatocyte injury (apoptosis), as assessed by histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and caspase-3 activation. The liver injury was augmented in rats administered LPS + APAP, in association with increased nuclear translocation of interferon-regulatory factor-1 (IRF1). In vitro, APAP augmented LPS/HSC-conditioned medium-induced inhibition of DNA and protein synthesis, apoptosis, and nuclear IRF1 in hepatocytes. LPS-stimulated HSCs produced interferon-beta (IFN-beta), and LPS/HSC + APAP-induced hepatocyte apoptosis was inhibited by anti-IFN-beta antibody. Finally, HSC-depleted mice produced significantly lower IFN-beta and tumor necrosis factor-alpha, exhibited less oxidative stress, and were protected from excessive injury due to high APAP dose (600 mg/kg), as well as LPS (5 mg/kg overnight) followed by APAP. In co-culture with or without LPS, HSCs increased expression of proinflammatory cytokines by Kupffer cells. These results suggest that HSCs play a critical role in APAP-induced liver injury without or with LPS preconditioning, and it involves INF-beta-IRF1 signaling. CI - Copyright (c) 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Rani, Richa AU - Rani R AD - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio. FAU - Sharma, Akanksha AU - Sharma A AD - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio. FAU - Wang, Jiang AU - Wang J AD - Department of Pathology, University of Cincinnati, Cincinnati, Ohio. FAU - Kumar, Sudhir AU - Kumar S AD - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio. FAU - Polaki, Usha S AU - Polaki US AD - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio. FAU - Gandhi, Chandrashekhar R AU - Gandhi CR AD - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: chandrashekhar.gandhi@cchmc.org. LA - eng GR - I01 BX001174/BX/BLRD VA/United States GR - P01 AI081678/AI/NIAID NIH HHS/United States GR - P30 DK078392/DK/NIDDK NIH HHS/United States GR - R01 DK054411/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20211223 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Cytokines) RN - 0 (Endotoxins) RN - 0 (Lipopolysaccharides) RN - 362O9ITL9D (Acetaminophen) SB - IM MH - Acetaminophen/metabolism/toxicity MH - Animals MH - *Chemical and Drug Induced Liver Injury/metabolism MH - *Chemical and Drug Induced Liver Injury, Chronic/metabolism MH - Cytokines/metabolism MH - Endotoxins/metabolism/toxicity MH - Hepatic Stellate Cells/metabolism MH - Hepatocytes/metabolism MH - Lipopolysaccharides/toxicity MH - Liver/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Rats PMC - PMC8895430 EDAT- 2021/12/27 06:00 MHDA- 2022/04/30 06:00 PMCR- 2023/03/01 CRDT- 2021/12/26 20:38 PHST- 2021/06/02 00:00 [received] PHST- 2021/10/27 00:00 [revised] PHST- 2021/11/29 00:00 [accepted] PHST- 2021/12/27 06:00 [pubmed] PHST- 2022/04/30 06:00 [medline] PHST- 2021/12/26 20:38 [entrez] PHST- 2023/03/01 00:00 [pmc-release] AID - S0002-9440(21)00529-0 [pii] AID - 10.1016/j.ajpath.2021.11.011 [doi] PST - ppublish SO - Am J Pathol. 2022 Mar;192(3):518-535. doi: 10.1016/j.ajpath.2021.11.011. Epub 2021 Dec 23.