Abstract
The adrenal steroid dehydroepiandrosterone (DHEA) and its analogs reduce growth of immortalized and malignant cell lines. We therefore explored their effects on the growth of airway smooth muscle, whose hyperplasia may lead to fixed airways obstruction and enhanced airways hyperresponsiveness in severe chronic asthma. DHEA and its potent analog 16α-bromoepiandrosterone dramatically reduced proliferation in primary cultures of rat tracheal smooth muscle stimulated with fetal bovine serum or platelet-derived growth factor. Growth inhibition was dose-dependent and could not be attributed to interference with glucose-6-phosphate dehydrogenase activity or cholesterol metabolism, as reported for immortalized or malignant cell lines, respectively. Expression of the early response gene c-fos remained intact, but DHEA and 16α-bromoepiandrosterone decreased DNA binding of the transcription factor activator protein-1, a later response important for expression of genes that mediate DNA synthesis and cell cycle progression. These results suggest that the nonglucocorticoid steroid DHEA and its analogs may impair activation of secondary growth response genes in a fashion analogous to that reported for glucocorticoids and that they may prove useful for treatment of asthmatic airway remodeling in the human.
Footnotes
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Send reprint requests to: Thomas P. Kennedy, M.D., Department of Internal Medicine, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232.
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↵1 This work was supported by the Charlotte-Mecklenberg Hospital Foundation (T.K.) and in part by NIH grant HL-48376 (T.M.M).
- Abbreviations:
- DHEA
- dehydroepiandrosterone
- DHEAS
- dehydroepiandrosterone sulfate
- 16α-BrEA or BrEA
- 16α-bromoepiandrosterone
- AP-1
- activator protein-1
- DMEM
- Dulbecco’s modified Eagle’s medium
- HBSS
- Hanks’ balanced salt solution
- FBS
- fetal bovine serum
- PDGF
- human platelet-derived growth factor-AA
- Tris
- Tris(hydroxymethyl)aminomethane
- MTT
- 3-[4,5-dimethylthiazol]-2yl-2,5-diphenyl tetrazolium bromide
- DPBS
- Dulbecco’s modified phosphate-buffered saline without Ca2+or Mg2+
- DMSO
- dimethylsulfoxide
- G6PDH
- glucose-6-phosphate dehydrogenase
- G6P
- d-glucose-6-phosphate
- SDS
- sodium docecyl sulfate
- HRP
- horseradish peroxidase
- IgG
- immunoglobulin G
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- CEB
- cell extraction buffer
- PI
- protease inhibitors
- NP-40
- Nonidet P-40
- NEB
- nuclear extraction buffer
- MAPK
- mitogen-activated protein kinase
- TRE
- TPA-response element
- GRE
- glucocorticoid response element
- NF-κB
- nuclear factor κB
- EMSA
- electrophoretic mobility shift assay
- Received July 28, 1997.
- Accepted January 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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