Pharmacological modulation of platelet-derived growth factor (B) mRNA expression in alveolar macrophages and adherent monocytes.
The macrophage profibrotic cytokine, Platelet Derived Growth Factor B [PDGF(B)], is thought to play a central role in orchestrating the fibrotic response in the pathogenesis of cryptogenic fibrosing alveolitis. In this study, we have asked if drugs that increase intracellular cAMP and are commonly administered to patients with lung disease have the ability to downregulate PDGF(B) mRNA. Incubation of human alveolar macrophages from healthy smokers in the presence of dibutyryl cAMP prevented the previously reported dexamethasone-induced increase in PDGF(B) mRNA (P < 0.05). Similarly, the combination of aminophylline (2.5 mM) and salbutamol (1 microM) prevented the adherence-dependent increase in PDGF(B) mRNA in adherent human peripheral blood monocytes (P < 0.05), whilst causing an increase in the mRNA expression of the cAMP-dependent gene c-fos (P = 0.059), and an increase in the intracellular concentration of cAMP (P = 0.05). Finally, the presence of a lower concentration of aminophylline (0.25 m) in conjunction with salbutamol (1 microM) also prevented the dexamethasone-induced increase in PDGF(B) mRNA in alveolar macrophages from healthy smokers (P < 0.05). Stimulation by these drugs was not associated with a change in the abundance of the mRNA of the house-keeping gene, glyceraldehyde-3-phosphate dehydrogenase. We speculate that drugs, which increase intracellular cAMP, may provide a novel therapeutic avenue whereby PDGF(B) expression in patients with cryptogenic fibrosing alveolitis may be reduced.
Kotecha
S
S
Department of Respiratory Medicine, St Mary's Hospital Medical School, London, UK.
Taylor
I K
IK
Shaw
R J
RJ
D001483:Base Sequence; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000096:biosynthesis; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis*; D013268:Stimulation, Chemical
D005938:Glucocorticoids; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D003907:Dexamethasone; D000242:Cyclic AMP