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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Neutrophils contribute to endotoxin enhancement of allyl alcohol hepatotoxicity.

Authors: Kinser, Shawn; Sneed, Rosie; Roth, Robert; Ganey, Patricia

Published In J Toxicol Environ Health A, (2004 Jun 25)

Abstract: Nontoxic doses of endotoxin (lipopolysaccharide, LPS) enhance the hepatotoxicity of many xenobiotic agents, including allyl alcohol. Systemic LPS exposure induces an inflammatory response, including accumulation and activation of neutrophils (PMNs) in the liver. The hypothesis that PMNs play a causal role in LPS enhancement of allyl alcohol hepatotoxicity was tested. Rats were pretreated with an anti-neutrophil antibody (anti-PMN immunoglobulin [lg]) to deplete circulating PMNs. Subsequently, they were given LPS or its vehicle, and 2 h later allyl alcohol was administered. The numbers of circulating and hepatic PMNs were decreased in rats pretreated with anti-PMN lg, and liver toxicity induced by cotreatment with LPS and allyl alcohol was attenuated. Treatment with allyl alcohol diminishes the concentration of reduced glutathione (GSH) in liver, raising the possibility that antioxidant defense was compromised in these livers. Accordingly, the hypothesis was tested that allyl alcohol-induced reduction in GSH renders liver cells more sensitive to reactive oxygen species produced by activated PMNs. Isolated hepatocytes were incubated with allyl alcohol in the presence and absence of isolated PMNs stimulated to produce reactive oxygen species. Allyl alcohol produced a concentration-dependent increase in ALT release from hepatocytes. Activated PMNs produced a statistically significant increase in cell killing that was so small it is unlikely to explain the role of PMNs in liver injury in vivo. To test the hypothesis that proteases released from activated PMNs increase the sensitivity of liver cells to allyl alcohol, isolated hepatocytes were incubated with medium from PMNs activated to undergo degranulation. Protease-containing medium from PMNs did not affect allyl alcohol-induced release of ALT from hepatocytes. Taken together, these results indicate that PMNs play a role in the potentiation of allyl alcohol toxicity by LPS. It is unlikely that PMNs contribute to this injury through release of reactive oxygen species or proteases, and other mechanisms must be involved.

PubMed ID: 15205035 Exiting the NIEHS site

MeSH Terms: Animals; Dose-Response Relationship, Drug; Drug-Induced Liver Injury/etiology; Drug-Induced Liver Injury/immunology*; Endotoxins/toxicity*; Environmental Pollutants/toxicity*; Hepatocytes/drug effects; Hepatocytes/enzymology; Lipopolysaccharides/toxicity; Male; Neutrophils/drug effects*; Neutrophils/physiology; Propanols/toxicity*; Rats; Rats, Sprague-Dawley

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