title: Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine.
abstract: Cotreatment of rats with nontoxic doses of ranitidine (RAN) and lipopolysaccharide (LPS) causes liver injury, and this drug-inflammation interaction might be a model for idiosyncratic adverse drug responses in humans. Both polymorphonuclear neutrophils (PMNs) and the hemostatic system have been shown to be important in the injury. We tested the hypothesis that PMNs cause liver injury by interacting with the hemostatic system and producing subsequent hypoxia. In rats cotreated with LPS/RAN, PMN depletion by anti-PMN serum reduced fibrin deposition and hypoxia in the liver. PMN depletion also reduced the plasma concentration of active plasminogen activator inhibitor-1 (PAI-1), a major down-regulator of the fibrinolytic system. This suggests that PMNs promote fibrin deposition by increasing PAI-1 concentration. PMNs were activated in the livers of LPS/RAN-cotreated rats as evidenced by increased staining for hypochlorous acid-modified proteins generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes. Antiserum against the PMN adhesion molecule CD18 protected against LPS/RAN-induced liver injury. Because CD18 is important for PMN transmigration and activation, these results suggest that PMN activation is required for the liver injury. Furthermore, anti-CD18 serum reduced biomarkers of hemostasis and hypoxia, suggesting the necessity for PMN activation in the interaction between PMNs and the hemostatic system/hypoxia. Liver injury, liver fibrin, and plasma PAI-1 concentration were also reduced by eglin C, an inhibitor of proteases released by activated PMNs. In summary, PMNs are activated in LPS/RAN-cotreated rats and participate in the liver injury in part by contributing to hemostasis and hypoxia.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, Food Safety and Toxicology Building, Michigan State University, Room 221, East Lansing, MI 48824. rothr@msu.edu.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Deng
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Jingtao
authors.initials: J
authors.lastname: Lu
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000991:Antithrombins / Q000378:metabolism; D018821:CD18 Antigens / Q000276:immunology; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects*; D006997:Hypochlorous Acid / Q000378:metabolism; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009593:Nitroimidazoles / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011506:Proteins / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism
chemical_list: D000991:Antithrombins; D018821:CD18 Antigens; D007106:Immune Sera; D008070:Lipopolysaccharides; D009593:Nitroimidazoles; D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D015842:Serine Proteinase Inhibitors; C028656:eglin proteinase inhibitors; C033815:pimonidazole; D006997:Hypochlorous Acid; D011899:Ranitidine; D005337:Fibrin; D005340:Fibrinogen; D000410:Alanine Transaminase; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase; D013917:Thrombin