SURFACTANT DOWN-REGULATES SYNTHESIS OF DNA AND INFLAMMATORY MEDIATORSIN NORMAL HUMAN LUNG FIBROBLASTS

The initial inflammatory event in the adult respiratory distress syndr ome (ARDS) is followed by fibroproliferation and a cascade of fibrobla st-derived mediators. Because lung fibroblasts may be exposed to surfa ctant as well as inflammatory cytokines during ARDS, we hypothesized t hat surfactant might modulate fibroblast activity. We previously demon strated that surfactant inhibited production of inflammatory cytokines from endotoxin-stimulated human alveolar macrophages. In the current study the effects of surfactant on normal human lung fibroblast prolif erative capacity and mediator production were examined. Both synthetic (Exosurf) and natural (Survanta) surfactant inhibited fibroblast [H-3 ]thymidine incorporation. Examination of pre-S-phase events indicated stimulation of the immediate response gene, c-fos, and no effect on th e G1/S cyclin, cyclin D1, suggesting that the surfactant block occurre d elsewhere before S phase. The antioxidant N-acetyl-L-cysteine (NAG), like surfactant, inhibited [H-3]thymidine incorporation. Furthermore, menadione, a generator of intracellular H2O2, stimulated fibroblast [ H-3]thymidine incorporation, and this was inhibited by surfactant. Int erleukin-1 (IL-1)-stimulated secretion of the inflammatory mediators, IL-6 and prostaglandin E(2), was also inhibited by surfactant. These d ata suggest that surfactant may modify lung fibroblast participation i n ARDS sequelae by downregulating DNA synthesis and secondary inflamma tory mediator production.