Skip Navigation



ToxSci Advance Access published online on September 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg222
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
76/1/237    most recent
kfg222v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hanumegowda, U. M.
Right arrow Articles by Roth, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hanumegowda, U. M.
Right arrow Articles by Roth, R. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received June 10, 2003; accepted August 12, 2003
© 2003 Society of Toxicology

Systems Toxicology

Basement Membrane and Matrix Metalloproteinases in Monocrotaline-Induced Liver Injury

Umesh M. Hanumegowda 1, Bryan L. Copple 1, Masabumi Shibuya 2, Ernst Malle 3, Patricia E. Ganey 1, and Robert A. Roth 1*

1 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
2 Institute of Medical Science, University of Tokyo, Tokyo, Japan
3 Institute of Medical Biochemistry and Molecular Biology, Karl-Franzens University, Graz, Austria

* To whom correspondence should be addressed. E-mail: rothr{at}msu.edu.


  Abstract

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 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 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 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 .


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 FASEB J.Home page
E. Dalakas, P. N. Newsome, D. J. Harrison, and J. N. Plevris
Hematopoietic stem cell trafficking in liver injury
FASEB J, August 1, 2005; 19(10): 1225 - 1231.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
Y. Ito, E. R. Abril, N. W. Bethea, and R. S. McCuskey
Inhibition of Matrix Metalloproteinases Minimizes Hepatic Microvascular Injury in Response to Acetaminophen in Mice
Toxicol. Sci., January 1, 2005; 83(1): 190 - 196.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.