Collagen-induced resistance to glucocorticoid anti-mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway.
Glucocorticoids (GCS) inhibit mitogenesis of airway smooth muscle (ASM) cells grown on plastic. We have now evaluated the effects of GCS on proliferation of ASM grown on extracellular matrix proteins (ECM) abundant in noninflamed airways (laminin) and in fibrotic asthmatic airways (collagen type I). Dexamethasone inhibited basic fibroblast growth factor (bFGF)-induced proliferation in cells maintained on laminin, but not collagen. Cells grown on collagen were resistant to the anti-mitogenic actions of fluticasone propionate. In addition, dexamethasone did not inhibit thrombin-induced proliferation. Thus, resistance induced by collagen is not dependent on the mitogen and appears to be a class effect on GCS. The inhibition of bFGF-induced granulocyte-macrophage colony-stimulating factor production was unaffected by the ECM type on which cells were grown. The impaired anti-mitogenic activity of GCS in cells maintained on collagen may be due to a lack of efficacy against the collagen-amplified mitogenesis, rather than any defect in responsiveness that is specific to glucocorticoid receptor mechanisms.
Bonacci
John V
JV
Department of Pharmacology, The University of Melbourne, Victoria 3010, Australia.
Harris
Trudi
T
Wilson
John W
JW
Stewart
Alastair G
AG
D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology*; D005109:Extracellular Matrix / Q000187:drug effects*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000473:pathology; D066298:In Vitro Techniques; D008938:Mitosis / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology
D005938:Glucocorticoids; D003094:Collagen