title: Lipopolysaccharide augments aflatoxin B(1)-induced liver injury through neutrophil-dependent and -independent mechanisms.
abstract: Exposure to small, noninjurious doses of the inflammagen, bacterial endotoxin (lipopolysaccharide, LPS) augments the toxicity of certain hepatotoxicants including aflatoxin B(1) (AFB(1)). Mediators of inflammation, in particular neutrophils (PMNs), are responsible for tissue injury in a variety of animal models. This study was conducted to examine the role of PMNs in the pathogenesis of hepatic injury after AFB(1)/LPS cotreatment. Male, Sprague-Dawley rats (250-350 g) were treated with either 1 mg AFB(1)/kg, ip or its vehicle (0.5% DMSO/saline), and 4 h later with either E. coli LPS (7. 4 x 10(6) EU/kg, iv) or its saline vehicle. Over a course of 6 to 96 h after AFB(1) administration, rats were killed and livers were stained immunohistochemically for PMNs. LPS resulted in an increase in PMN accumulation in the liver that preceded the onset of liver injury. To assess if PMNs contributed to the pathogenesis, an anti-PMN antibody was administered to reduce PMN numbers in blood and liver, and injury was evaluated. Hepatic parenchymal cell injury was evaluated as increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum and from histologic examination of liver sections. Biliary tract alterations were evaluated as increased concentration of serum bile acids and activities of gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), and 5'-nucleotidase (5'-ND) in serum. Neutrophil depletion protected against hepatic parenchymal cell injury caused by AFB(1)/LPS cotreatment but not against markers of biliary tract injury. This suggests that LPS augments AFB(1) hepatotoxicity through two mechanisms: one of which is PMN-dependent, and another that is not.
authors.affiliation: Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, and Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Barton
authors.forename: P E
authors.initials: PE
authors.lastname: Ganey
authors.forename: R A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D015720:5'-Nucleotidase / Q000097:blood; D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004357:Drug Synergism; D004926:Escherichia coli; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D016604:Aflatoxin B1; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase