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.
Highlights
We demonstrate that Chtx protects mice from APAP-induced toxicity and mortality by reducing centrilobular hepatic damage and decreased inflammation in liver, which was further associated with increased neutrophil migration in peritoneum and inhibition of inflammasome pathway in liver
The present study highlights the critical role of bacterial endotoxin LPS and microbiota in mediating APAP-induced hepatotoxicity and it demonstrates that a carbohydrate Chtx, an LPS antagonist, induces protection against APAPinduced liver failure in mice
These findings offer credence to the notion that APAP essentially leads to release of dangerassociated molecular patterns (DAMPs) by necrosis of liver cells and that further inflammation and mortality are essentially mediated by endogenous LPS from microbiota owing to a leaky gut.[36,37,38]
Summary
Successful demonstration of reduced APAP toxicity, using synthetic TLR4 antagonists[14,18] and inhibitor of lipopolysaccharide-binding protein,[19] have further strengthened the TLR4-LPS nexus in APAP-induced liver dysfunction. A recent report demonstrating that impairment of macrophage switching from classically activated/pro-inflammatory phenotype to alternatively activated/wound repair phenotype reduces APAP toxicity, emphasizing the critical role played by alternatively activated macrophages in recovery of APAPinduced liver damage.[27] This attracted our attention because we had shown that Chtx induces alternate activation of macrophages through its binding to TLR4. We demonstrate that Chtx protects mice from APAP-induced toxicity and mortality by reducing centrilobular hepatic damage and decreased inflammation in liver, which was further associated with increased neutrophil migration in peritoneum and inhibition of inflammasome pathway in liver. We describe that low doses of LPS and APAP act synergistically, and mutually potentiate local (liver) and systemic inflammation leading to mortality in mice, and neutralization of Chtx reverses the toxicity mutually induced by APAP and LPS in this model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
