Thrombin induces calcium independent phospholipase A₂ (iPLA₂) activity and neutrophil adherence in human small airways epithelial cells

Abstract

The presence of polymorphonuclear leukocytes (PMN) in the airways is a hallmark of many inflammatory conditions including ARDS, COPD and cystic fibrosis. In the event of a breach in the epithelial or endothelial cell barrier, PMN can migrate from the circulation to the airway lumen. This involves a series of steps including PMN adherence and transmigration through the vascular endothelium into the interstitial tissue, followed by a similar sequence of events used to cross the airway epithelium and enter the lumen. We have determined previously that stimulation of human small airway epithelial cells (HSAEC) with thrombin results in increased iPLA2 activity that is inhibited by the iPLA2 selective inhibitor bromoenol lactone (BEL). Further, activation of iPLA2 results in increased arachidonic acid and prostacyclin release. We also found that PMN adherence to thrombin‐stimulated HSAEC is increased 25 fold over adherence to unstimulated cells. Pretreatment with of HSAEC with BEL or PMN with CV3988, a PAF receptor antagonist, leads to inhibition of thrombin‐stimulated PMN adherence. This indicates that inhibition of iPLA2 or blocking the PAF receptor may be effective tools in limiting the cascade of neutrophil adherence, inflammatory mediator production and tissue destruction in cases of acute lung inflammation.