Neither platelet activating factor nor leukotrienes are critical mediators of liver injury after lipopolysaccharide administration.
The intravenous administration of lipopolysaccharide (LPS) to rats results in liver lesions characterized by the infiltration of both platelets and neutrophils into the liver and by midzonal hepatocellular necrosis. The liver injury is dependent on neutrophils, platelets and the coagulation system, as removal or inhibition of any of these components inhibits the development of hepatocellular necrosis. Platelet activating factor (PAF) and the cysteinyl leukotrienes (LTs) are potent inflammatory lipids that are critical for the development of some LPS-mediated alterations. To test the hypothesis that PAF, alone or in combination with LTs, contributes to the development of liver injury during LPS exposure, we conducted studies with the PAF receptor antagonist, WEB 2086, and the 5-lipoxygenase inhibitor, Zileuton. Female, Sprague-Dawley rats were pretreated with WEB 2086 (10 mg/kg, i.p.) alone or with Zileuton (40 mg/kg, p.o.) 1 h before the administration of LPS (4 mg/kg, i.v.) or its saline vehicle. Treatment with WEB 2086, alone or in combination with Zileuton, did not inhibit LPS-mediated hepatic neutrophil infiltration or liver injury, as assessed by histologic evaluation and increases in plasma alanine aminotransferase activity. Pretreatment with these agents also had no effect on the activation of the coagulation system or on the thrombocytopenia induced by LPS. These results suggest that PAF, alone or in combination with 5-lipoxygenase products, is not a critical mediator of LPS-induced hepatocellular injury in this model.
Pearson
J M
JM
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, Michigan State University, East Lansing 48824, USA.
Bailie
M B
MB
Fink
G D
GD
Roth
R A
RA
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005340:Fibrinogen / Q000032:analysis / Q000187:drug effects; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D015289:Leukotrienes / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010972:Platelet Activating Factor / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000188:drug therapy / Q000517:prevention & control; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D001381:Azepines; D015289:Leukotrienes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C052518:WEB 2086; D005340:Fibrinogen; D000410:Alanine Transaminase; C063449:zileuton; D006918:Hydroxyurea