Modification of Alveolar Macrophage Function with Bis-Basic Ethers of Fluorene and Fluoren-9-Substituted Derivatives

Details

• Personal Author:
  Barger Mw ; Castranova, Vincent ; Cheng YH ; Lewis, Daniel M. ; Ma JKH ; Ma JYC ; Xin WF
• Description:
  Bis-basic ethers of fluorene and fluoren-9-substituted derivatives such as tilorone have been reported to inhibit silica-induced fibrosis in rats. The potential antifibrotic potency of 2,7-bis(diethylamino)ethoxy 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 exposure has been linked to the development of pulmonary fibrosis, the present study was carried out to determine the inhibitory effects of these compounds on rat AM activity in vitro. The following parameters were monitored. (1) cellular viability; (2) zymosan-induced respiratory burst activity (superoxide and hydrogen peroxide release, chemiluminescence, 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 when incubated with AM for 30 min, but significantly inhibited zymosan-induced macrophage respiratory burst activity. The inhibitory effect of 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-stimulated 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 addition, these drugs were also shown to impair human fibroblast proliferation 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 activities including oxygen consumption, superoxide release, hydrogen peroxide secretion, chemiluminescence, IL-1 release, and proliferation. The ability of these bis-basic ethers to modify AM and fibroblast functions in vitro suggests that further investigation of their reported antifibrotic potency in vivo is warranted. [Description provided by NIOSH]
• Subjects:
  Growth Hypersensitivity Laboratories Lung Lung Diseases Microbiology Occupational Health Respiratory System Respiratory Tract Diseases Safety Silicosis

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• Keywords:
  Antifibrotic Agents Author Keywords: Alveolar Macrophages Bis-basic Ethers Of Fluorene Derivatives Cell-function Cell-metabolism Cellular-function Cellular-reactions Chemical-hypersensitivity Chemical-inhibition Fibrogenesis Growth-factors Growth-inhibitors Laboratory-animals Lung-cells Lung-disorders Lung-fibrosis Lung-irritants Microscopic-analysis Oxygen-transport Pulmonary-function Pulmonary-system-disorders Silicosis

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• ISSN:
  0190-2148
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DRDS - Division of Respiratory Disease Studies
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  21
• Issue:
  5
• NIOSHTIC Number:
  nn:20035139
• Citation:
  Exp Lung Res 1995 Sep-Oct; 21(5):771-790
• CAS Registry Number:
  Diethyl ether (CAS RN 60-29-7) ; Silica (CAS RN 7631-86-9)
• Federal Fiscal Year:
  1995
• Peer Reviewed:
  True
• Source Full Name:
  Experimental Lung Research
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2e746cb8d45fc7179fc545efad3f29792426a6ce0d5ac6c2b3ef10670c0c1aa9c09916d7f69dbc8c269b598fe21d32dc92c310db0b2098802ae87abb3c2bda16
• Download URL:
  https://stacks.cdc.gov/view/cdc/187092/cdc_187092_DS1.pdf
• File Type:
  [PDF - 1000.18 KB ]