Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor.
TNF-alpha is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-alpha to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-alpha concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-alpha in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-alpha, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-alpha plays a role in the hepatocellular necrosis and apoptosis that accompany D-GalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.
Solorzano
C C
CC
Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
Ksontini
R
R
Pruitt
J H
JH
Hess
P J
PJ
Edwards
P D
PD
Kaibara
A
A
Abouhamze
A
A
Auffenberg
T
T
Galardy
R E
RE
Vauthey
J N
JN
Copeland
E M
EM
Edwards
C K
CK
Lauwers
G Y
GY
Clare-Salzler
M
M
MacKay
S L
SL
Moldawer
L L
LL
Lazarus
D D
DD
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D003208:Concanavalin A / Q000633:toxicity; D004151:Dipeptides / Q000633:toxicity*; D004357:Drug Synergism; D005688:Galactosamine / Q000737:chemistry / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000293:injuries; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000633:toxicity*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000737:chemistry* / Q000633:toxicity*
D004151:Dipeptides; D008070:Lipopolysaccharides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D005688:Galactosamine; D008666:Metalloendopeptidases