Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure.
Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.
Yee
Steven B
SB
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, East Lansing, Michigan 48824, USA.
Hanumegowda
Umesh M
UM
Hotchkiss
Jon A
JA
Ganey
Patricia E
PE
Roth
Robert A
RA
D000818:Animals; D001419:Bacteria / Q000378:metabolism; D018925:Chemokines / Q000097:blood; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D016686:Monocrotaline / Q000378:metabolism / Q000633:toxicity*; D009504:Neutrophils / Q000502:physiology*; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011763:Pyrrolizidine Alkaloids; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline