HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Van Lint, P. Articles by Libert, C. Search for Related Content PubMed PubMed Citation Articles by Van Lint, P. Articles by Libert, C.

Resistance of Collagenase-2 (Matrix Metalloproteinase-8)-Deficient Mice to TNF-Induced Lethal Hepatitis¹

Philippe Van Lint^2,3,*, Ben Wielockx^2,4,*, Leen Puimège^*, Agnès Noël, Carlos López-Otin and Claude Libert^*

^* Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology-Ghent University, Ghent, Belgium; Laboratory of Biology of Tumors and Development, University of Liège, Liège, Belgium; and Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Spain

Acute fulminant liver failure is a serious worldwide health problem. Despite maximal supportive intensive care treatment, the disease offers a poor prognosis, with mortality rates of >80%. We have previously shown that a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) confers complete protection in a mouse model of TNF-induced lethal hepatitis, thereby suggesting the possibility of protecting cancer patients against the deleterious side effects of TNF therapy. In our search for the individual matrix metalloproteinases involved, we found that the recently generated MMP-8-deficient mice are significantly protected against TNF-induced acute hepatitis. In contrast to their wild-type counterparts, MMP-8-null mice display very little hepatocyte necrosis and apoptosis, resulting in a much better survival outcome. We found that these animals clearly display impaired leukocyte influx into the liver and no release of the neutrophil-specific, LPS-induced CXC chemokine. Our findings provide evidence that MMP-8 plays an essential role in acute liver failure and might be a promising new target for the treatment for this illness.