title: Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice.
abstract: Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1β as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1β and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1β in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose.
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, India.
authors.forename: P K
authors.initials: PK
authors.lastname: Barman
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, India.
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, India.
authors.forename: B K
authors.initials: BK
authors.lastname: Prusty
authors.affiliation: Translational Research Group, Institute of Life Sciences, Bhubaneswar, India.|Manipal University, Manipal, India.
authors.forename: S
authors.initials: S
authors.lastname: Suklabaidya
authors.affiliation: Translational Research Group, Institute of Life Sciences, Bhubaneswar, India.
authors.forename: S
authors.initials: S
authors.lastname: Senapati
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, India.
authors.forename: B
authors.initials: B
authors.lastname: Ravindran
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009844:Oligosaccharides / Q000494:pharmacology*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009844:Oligosaccharides; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; C050523:chitohexaose