The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia.
Tumor necrosis factor-alpha (TNF-alpha) is released from the cell surface by cleavage of pro-TNF-alpha by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-alpha, but also to enhance the surface expression of TNF-alpha and TNF-alpha receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (-20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF-alpha release (P <.001), but did not influence the increase in monocyte-bound TNF-alpha. In addition, GI5402 attenuated the rise in plasma-soluble TNF-alpha receptors types I and II after LPS injection (both P <.001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF-alpha receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF-alpha is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF-alpha and TNF-alpha receptor number.
Dekkers
P E
PE
Academic Medical Center, University of Amsterdam, Laboratory of Experimental Internal Medicine, Amsterdam, The Netherlands. P.E.Dekkers@AMC.UVA.NL
Lauw
F N
FN
ten Hove
T
T
te Velde
A A
AA
Lumley
P
P
Becherer
D
D
van Deventer
S J
SJ
van der Poll
T
T
D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha