Linked Life Data

20637792

Source:http://linkedlifedata.com/resource/pubmed/id/20637792

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2010-8-27
pubmed:abstractText
Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1beta to increase injury, mice were given pharmacological doses of IL-1beta after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1096-0333
pubmed:author
pubmed:copyrightInfo
2010 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
247
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
169-78
pubmed:dateRevised
2011-9-19
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury.
pubmed:affiliation
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural