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Pharmacological modulation of platelet-derived growth factor (B) mRNA expression in alveolar macrophages and adherent
S Kotecha1, I K Taylor, R J Shaw
1Department of Respiratory Medicine, St Mary's Hospital Medical School, London, UK.
Abstract:
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.
Insights
Drugs that increase intracellular cAMP, like aminophylline and salbutamol, can reduce Platelet Derived Growth Factor B (PDGF(B)) mRNA. This suggests a potential new therapy for cryptogenic fibrosing alveolitis by targeting PDGF(B) expression.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Pharmacology
Background:
- Platelet Derived Growth Factor B (PDGF(B)) is a key cytokine in the fibrotic response of cryptogenic fibrosing alveolitis.
- Current therapies for lung diseases often involve drugs that increase intracellular cyclic adenosine monophosphate (cAMP).
Purpose of the Study:
- To investigate if drugs increasing intracellular cAMP can downregulate PDGF(B) mRNA expression.
- To explore potential therapeutic strategies for cryptogenic fibrosing alveolitis by modulating PDGF(B).
Main Methods:
- Human alveolar macrophages and peripheral blood monocytes from healthy smokers were incubated with various agents.
- Treatments included dibutyryl cAMP, dexamethasone, aminophylline, and salbutamol.
- PDGF(B) mRNA levels were quantified, alongside intracellular cAMP concentrations and c-fos mRNA expression.
Main Results:
- Dibutyryl cAMP prevented dexamethasone-induced increases in PDGF(B) mRNA in alveolar macrophages.
- Aminophylline and salbutamol combination inhibited adherence-dependent PDGF(B) mRNA increase in monocytes and increased intracellular cAMP.
- This drug combination also prevented dexamethasone-induced PDGF(B) mRNA increases in alveolar macrophages.
Conclusions:
- Drugs that elevate intracellular cAMP show potential in downregulating PDGF(B) mRNA expression.
- These findings suggest a novel therapeutic approach for cryptogenic fibrosing alveolitis by targeting PDGF(B).