MODIFICATION OF ALVEOLAR MACROPHAGE FUNCTION WITH BIS-BASIC ETHERS OFFLUORENE AND FLUOREN-9-SUBSTITUTED DERIVATIVES

Bis-basic ethers of fluorene and fluoren-9-substituted derivatives suc h as tilorone have been reported to inhibit silica-induced fibrosis in rats. The potential antifibrotic potency of 2,7-bis(diethylamino)etho xy fluorene (F-9-ol), fluorenone (F-9-one), fluorenoxime (F-9-oxime), and fluorenol (F-9-ol) was F-9-oxime > F-9-one similar to F-9-H,H much greater than F-9-ol. Since the release of reactive oxygen species and growth factors from alveolar macrophages (AM) in response to silica e xposure has been linked to the development of pulmonary fibrosis, the present study was carried out to determine the inhibitory effects of t hese compounds on rat AM activity in vitro. The following parameters w ere monitored. (1) cellular viability; (2) zymosan-induced respiratory burst activity (superoxide and hydrogen peroxide release, chemilumine scence, and oxygen consumption) of AM; (3) drug binding to AM; and (4) lipopolysaccharide (LPS)-stimulated interleukin-1 (IL-1) release from AM. The bis-basic ethers, at 40 mu M, did not affect cell viability w hen incubated with AM for 30 min, but significantly inhibited zymosan- induced macrophage respiratory burst activity. The inhibitory effect o f these agents was F-9-oxime > F-9-one similar to F-9-H,H much greater than F-9-ol. Binding of these drugs to AM war time and dose dependent , and exhibited the following binding affinity: F-9-oxime > F-9-one > F-9-H,H > F-9-ol. F-9-ol. F-9-oxime was shown to inhibit LPS-stimulate d IL-1 release by AM in a dose-dependent manner. This inhibition of IL -1 release by AM cannot be explained as a decrease in viability. In ad dition, these drugs were also shown to impair human fibroblast prolife ration in response to serum stimuli without impairing cell viability. These results indicate a positive correlation between drug binding to AM or other cell types and their inhibitory effects on cellular activi ties including oxygen consumption, superoxide release, hydrogen peroxi de secretion, chemiluminescence, IL-1 release, and proliferation. The ability of these bis-basic ethers to modify AM and fibroblast function s in vitro suggests that further investigation of their reported antif ibrotic potency in vivo is warranted.