EFFECT OF NEUTROPHIL SERINE PROTEINASES AND DEFENSINS ON LUNG EPITHELIAL-CELLS - MODULATION OF CYTOTOXICITY AND IL-8 PRODUCTION

Neutrophil accumulation in the lung may contribute to tissue injury as observed in inflammatory diseases, Both oxidative and non-oxidative m echanisms are involved in neutrophil-mediated tissue injury, Non-oxida tive mechanisms include the release of neutrophil granule proteins suc h as the serine proteinases elastase and cathepsin G, and the non-enzy matic defensins, Because stimulated neutrophils are thought to release their products simultaneously, we investigated possible interactions between purified defensins and serine proteinases with respect to indu ction of cellular injury and their ability to induce interleukin-8 (IL -8) synthesis in cells of the lung epithelial cell line A549. Whereas defensins induced cell lysis, elastase and cathepsin G induced detachm ent of A549 cells, Go-incubation of elastase and cathepsin G revealed an additive effect on detachment, whereas defensins inhibited serine p roteinase-induced detachment. Vice verse, both serine proteinases redu ced defensin-induced cell lysis. Furthermore, elastase and cathepsin G prevented defensin-induced IL-8 synthesis. In contrast, no inhibitory interaction between cathepsin G and defensins was observed with respe ct to their antibacterial activity. The results from this study indica te that, at sites of inflammation, neutrophil-mediated injury might be regulated by interactions between released defensins and serine prote inases.