The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-α (TNF-α) and TNF-α 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 G15402 (100 mg) or matching placebo. G15402 strongly reduced LPS-induced TNF-alpha release (P < .001), but did not influence the increase in monocyte-bound TNF-alpha, In addition, G15402 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. (C) 1999 by The American Society of Hematology.