ToxSci Advance Access originally published online on September 11, 2003
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Toxicological Sciences 76, 237-246 (2003)
Copyright © 2003 by the Society of Toxicology
SYSTEMS TOXICOLOGY |
Basement Membrane and Matrix Metalloproteinases in Monocrotaline-Induced Liver Injury
* Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824;
Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Institute of Medical Biochemistry and Molecular Biology, Karl-Franzens University, Graz, Austria
Monocrotaline (MCT) is a pyrrolizidine alkaloid that causes liver injury in animals. In rats, injury is characterized by sinusoidal endothelial cell (SEC) damage and centrilobular parenchymal cell necrosis. Loss of endothelium is a possible outcome of the action of matrix metalloproteinases (MMPs), specifically MMP-9 from neutrophils and SECs and MMP-2 from SECs, on basement membrane collagen. Accordingly, the dynamics of MMPs in MCT-induced SEC damage were studied. Rats were treated with MCT (300 mg/kg, ip), and livers were collected at 8, 12, and 18 h. Immunofluorescence analysis of frozen sections of livers from MCT-treated rats revealed a progressive reduction in basement membrane heparan sulfate proteoglycan and collagen IV. A time-dependent increase in total type IV collagenase activity and MMP-9 content occurred in the livers of MCT-treated rats, as measured by fluorescent collagenase activity assay and gelatin zymography, respectively. Progressive neutrophil accumulation and activation in the liver after MCT treatment were demonstrated by an increased activity of myeloperoxidase and pronounced staining for hypochlorite-modified proteins generated via the myeloperoxidase–hydrogen peroxide–halide system. However, neutrophil depletion did not protect against MCT-induced SEC injury. Treatment of NP-26 cells, a sinusoidal endothelial cell line, with MCT resulted in dose-dependent release of MMP-9 from the cells. The results demonstrate the degradation of basement membrane components with a concurrent increase in the amount and activity of MMP-9, likely originating from sinusoidal endothelial cells, neutrophils, and probably other cell types. This suggests the possibility of a role for MMPs in the SEC detachment and loss that occurs during MCT hepatotoxicity.
Key Words: sinusoidal endothelial cells; NP-26 cells; collagen IV; PMNs; myeloperoxidase–hydrogen peroxide–halide system.
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