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-1ß 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-1ß 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-1ß 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.
Subject(s)
Acetaminophen/toxicity , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Hepatitis, Animal/prevention & control , Liver/drug effects , Oligosaccharides/pharmacology , Acetaminophen/antagonists & inhibitors , Animals , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/mortality , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Drug Administration Schedule , Gene Expression Regulation , Hepatitis, Animal/chemically induced , Hepatitis, Animal/genetics , Hepatitis, Animal/mortality , Injections, Intraperitoneal , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/toxicity , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Neutrophil Infiltration/drug effects , Survival Analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Retinoic acid syndrome is a novel complication of therapy with all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APML). Primarily the syndrome consists of fever and respiratory distress. Additional features include weight gain, oedema over lower extremities, pleural or pericardial effusion and hypotension. We report electrophysiological changes in a 16 year old patient with acute promyelocytic leukemia following treatment with ATRA. Such an unusual complication is a rarity and to the best of our knowledge has not been previously reported.
