H. Hank Simms

Transmigration across a lung epithelial monolayer delays apoptosis of polymorphonuclear leukocytes

BACKGROUND Suppression of polymorphonuclear leukocyte (PMNL) apoptosis may cause or exaggerate acute lung injury that is associated with the acute respiratory distress syndrome. We hypothesized that transepithelial migration would modulate PMNL apoptosis. METHOD PMNLs that were freshly purified from normal volunteers were allowed to migrate across transwell membranes alone or coated with monolayers of human lung epithelial cells in response to chemoattractants (interleukin-8, formyl-methionylleucylphenylalanine and leukotriene B(4)). We assessed for migration efficiency, apoptosis, and functional activity of the PMNLs. Changes in the expression of genes modulating PMNL apoptosis were examined with messenger RNA and protein analyses. RESULTS Transepithelial migration caused a significant decrease in the percentage of apoptotic PMNLs (interleukin-8; from 31% to 16% at 8 hours; P<.01). This apoptotic delay was sustained to at least 20 hours that was associated with prolongation of PMNL functional activity and independent of chemoattractant-type. Gene and protein expression levels of the antiapoptotic proteins Mcl-1 and 14-3-3 zeta were either augmented or preserved by interleukin-8 treatment alone and after transepithelial migration. CONCLUSION Our data reveal, for the first time, the important role of transepithelial migration in the modulation of PMNL apoptosis and may provide insights into possible novel targets for the regulation of PMNL apoptosis during lung inflammation and injury.