PMID- 10498596
OWN - NLM
STAT- MEDLINE
DCOM- 19991104
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 94
IP  - 7
DP  - 1999 Oct 1
TI  - The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis 
      factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia.
PG  - 2252-8
AB  - 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.
FAU - Dekkers, P E
AU  - Dekkers PE
AD  - Academic Medical Center, University of Amsterdam, Laboratory of Experimental 
      Internal Medicine, Amsterdam, The Netherlands. P.E.Dekkers@AMC.UVA.NL
FAU - Lauw, F N
AU  - Lauw FN
FAU - ten Hove, T
AU  - ten Hove T
FAU - te Velde, A A
AU  - te Velde AA
FAU - Lumley, P
AU  - Lumley P
FAU - Becherer, D
AU  - Becherer D
FAU - van Deventer, S J
AU  - van Deventer SJ
FAU - van der Poll, T
AU  - van der Poll T
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Adult
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Endotoxemia/chemically induced/*drug therapy/immunology
MH  - Granulocytes/drug effects/immunology
MH  - Humans
MH  - Kinetics
MH  - Lipopolysaccharides/toxicity
MH  - Male
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Monocytes/drug effects/immunology
MH  - Receptors, Tumor Necrosis Factor/*biosynthesis
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
EDAT- 1999/09/25 00:00
MHDA- 1999/09/25 00:01
CRDT- 1999/09/25 00:00
PHST- 1999/09/25 00:00 [pubmed]
PHST- 1999/09/25 00:01 [medline]
PHST- 1999/09/25 00:00 [entrez]
AID - S0006-4971(20)71149-3 [pii]
PST - ppublish
SO  - Blood. 1999 Oct 1;94(7):2252-8.