Resistance of collagenase-2 (matrix metalloproteinase-8)-deficient mice to TNF-induced lethal hepatitis.
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.
Van Lint
Philippe
P
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology-Ghent University, Ghent, Belgium. philippe.vanlint@dmbr.ugent.be
Wielockx
Ben
B
Puimège
Leen
L
Noël
Agnès
A
López-Otin
Carlos
C
Libert
Claude
C
D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*
D054365:Chemokine CXCL5; D019743:Chemokines, CXC; C094739:Cxcl5 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020784:Matrix Metalloproteinase 8