Surfactant downregulates synthesis of DNA and inflammatory mediators in normal human lung fibroblasts.
The initial inflammatory event in the adult respiratory distress syndrome (ARDS) is followed by fibroproliferation and a cascade of fibroblast-derived mediators. Because lung fibroblasts may be exposed to surfactant as well as inflammatory cytokines during ARDS, we hypothesized that surfactant might modulate fibroblast activity. We previously demonstrated 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 proliferative capacity and mediator production were examined. Both synthetic (Exosurf) and natural (Survanta) surfactant inhibited fibroblast [3H]thymidine incorporation. Examination of pre-S-phase events indicated stimulation of the immediate response gene, c-fos, and no effect on the G1/S cyclin, cyclin D1, suggesting that the surfactant block occurred elsewhere before S phase. The antioxidant N-acetyl-L-cysteine (NAC), like surfactant, inhibited [3H]thymidine incorporation. Furthermore, menadione, a generator of intracellular H2O2, stimulated fibroblast [3H]thymidine incorporation, and this was inhibited by surfactant. Interleukin-1 (IL-1)-stimulated secretion of the inflammatory mediators, IL-6 and prostaglandin E2, was also inhibited by surfactant. These data suggest that surfactant may modify lung fibroblast participation in ARDS sequelae by downregulating DNA synthesis and secondary inflammatory mediator production.
Thomassen
M J
MJ
Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Ohio 44195-5038, USA.
Antal
J M
JM
Barna
B P
BP
Divis
L T
LT
Meeker
D P
DP
Wiedemann
H P
HP
D000975:Antioxidants / Q000494:pharmacology; D001688:Biological Products; D002478:Cells, Cultured; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005233:Fatty Alcohols / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D010767:Phosphorylcholine; D011092:Polyethylene Glycols / Q000494:pharmacology; D011663:Pulmonary Surfactants / Q000494:pharmacology / Q000502:physiology*; D012016:Reference Values
D000975:Antioxidants; D001688:Biological Products; D004338:Drug Combinations; D005233:Fatty Alcohols; D018836:Inflammation Mediators; D011663:Pulmonary Surfactants; D010767:Phosphorylcholine; D011092:Polyethylene Glycols; D004247:DNA; C047049:dipalmitoylphosphatidylcholine, hexadecanol, tyloxapol drug combination; C072197:beractant