Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membrane.
1. In acute respiratory distress syndrome (ARDS) induced by endotoxins, a high production of inflammatory mediators by microvascular lung endothelial cells (LMVEC) can be observed. Activation of cells by endotoxins may result in elevated secretion of phospholipase A(2) (sPLA(2)) which is thought to contribute to tissue damage. The present study was undertaken to investigate the role of sPLA(2) in chemokine production in human lung microvascular endothelial cells (LMVEC) stimulated with the endotoxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In particular, we investigated the effects of sPLA(2) inhibitors, specifically, the extracellular PLA(2) inhibitors (ExPLIs), composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers, and LY311727, a specific inhibitor of non-pancreatic sPLA(2). 2. ExPLIs markedly inhibited LPS and LTA induced production and mRNA expression of the neutrophile attracting chemokines IL-8, Gro-alpha and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-kappaB by LPS but not its activation by TNF-alpha or IL-1. 3. Endotoxin mediated chemokine production in LMVEC seems not to involve PLA(2) activity, since LPS stimulation was not associated with activation of intracellular or secreted PLA(2). It therefore seems that the inhibitory effect of the ExPLIs was not due to their PLA(2) inhibiting capacity. This was supported by the finding that the LPS-induced chemokine production was not affected by the selective sPLA(2) inhibitor LY311727. 4. It is proposed that the ExPLIs may be considered a prototype of potent suppressors of specific endotoxin-induced inflammatory responses, with potential implications for the therapy of subsequent severe inflammation.
Beck
G Ch
GCh
Institute of Anaesthesiology, University of Mannheim, Germany. grietje.beck@anaes.ma.uni-heidelberg.de
Yard
B A
BA
Schulte
J
J
Oberacker
R
R
van Ackern
K
K
van Der Woude
F J
FJ
Krimsky
M
M
Kaszkin
M
M
Yedgar
S
S
D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism
D015815:Cell Adhesion Molecules; D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010714:Phosphatidylethanolamines; D006820:Hyaluronic Acid; D010741:Phospholipases A