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-α and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-κB by LPS but not its activation by TNF-α 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.