PHARMACOLOGICAL MODULATION OF PLATELET-DERIVED GROWTH-FACTOR-(B) MESSENGER-RNA 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 fibr otic response in the pathogenesis of cryptogenic fibrosing alveolitis. In this study, we have asked if drugs that increase intracellular cAM P and are commonly administered to patients with lung disease have the ability to downregulate PDGF(B) mRNA, Incubation of human alveolar ma crophages from healthy smokers in the presence of dibutyryl cAMP preve nted the previously reported dexamethasone-induced increase in PDGF(B) mRNA (P<0.05). Similarly, the combination of aminophylline (2.5 mM) a nd salbutamol (1 mu M) prevented the adherence-dependent increase in P DGF(fl) mRNA in adherent human peripheral blood monocytes (P<0.05), wh ilst causing an increase in the mRNA expression of the cAMP-dependent gene c-fos (P=0.059), and an increase in the intracellular concentrati on of cAMP (P=0.05). Finally, the presence of a lower concentration of aminophylline (0.25 m) in conjunction with salbutamol (1 mu M) also p revented the dexamethasone-induced increase in PDGF(B)) mRNA in alveol ar macrophages from healthy smokers (P<0.05). Stimulation by these dru gs was not associated with a change in the abundance of the mRNA of th e house-keeping gene, glyceraldehyde-3-phosphate dehydrogenase. We spe culate that drugs, which increase intracellular cAMP, may provide a no vel therapeutic avenue whereby PDGF(B) expression in patients with cry ptogenic fibrosing alveolitis may be reduced.