Liver inflammation during monocrotaline hepatotoxicity.
Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that causes hepatotoxicity in humans and animals. Human exposure occurs from consumption of contaminated grains and herbal teas and medicines. Intraperitoneal injection (i.p.) of 300 mg/kg MCT in rats produced time-dependent hepatic parenchymal cell (HPC) injury beginning at 12 h. At this time, an inflammatory infiltrate consisting of neutrophils (PMNs) appeared in areas of hepatocellular injury, and activation of the coagulation system occurred. PMN accumulation was preceded by up-regulation of the PMN chemokines cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) in the liver. The monocyte chemokine, monocyte chemoattractant protein-1 (MCP-1), was also upregulated. Inhibition of Kupffer cell function with gadolinium chloride (GdCl(3)) significantly reduced CINC-1 protein in plasma after MCT treatment but had no effect on hepatic PMN accumulation. Since inflammation can contribute to either pathogenesis or resolution of tissue injury, we explored inflammatory factors as a contributor to MCT hepatotoxicity. To test the hypothesis that PMNs contribute to MCT-induced HPC injury, rats were depleted of PMNs with a rabbit anti-PMN serum prior to MCT treatment. Anti-PMN treatment reduced hepatic PMN accumulation by 80% but had no effect on MCT-induced HPC injury or activation of the coagulation system. To test the hypothesis that Kupffer cells and/or tumor necrosis factor-alpha (TNF-alpha) are required for MCT-induced HPC injury, rats were treated with either GdCl(3) to inhibit Kupffer cell function or pentoxifylline (PTX) to prevent synthesis of TNF-alpha. Neither treatment prevented MCT-induced HPC injury. Results from these studies suggest that PMNs, Kupffer cells and TNF-alpha are not critical mediators of MCT hepatotoxicity. Accordingly, although inflammation occurs in the liver after MCT treatment, it is not required for HPC injury and possibly occurs secondary to hepatocellular injury.
Copple
Bryan L
BL
Institute for Environmental Toxicology, B-346 Life Sciences Building, Michigan State University, East Lansing, MI 48824, USA.
Ganey
Patricia E
PE
Roth
Robert A
RA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; C475829:CXCL1 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline; D006493:Heparin; D005682:Gadolinium; C038958:gadolinium chloride; D010431:Pentoxifylline