Pharmacological modulation of the bradykinin-induced differentiation of human lung fibroblasts: effects of budesonide and formoterol.

Objective. Bradykinin (BK) induces differentiation of lung fibroblasts into myofibroblasts, which play an important role in extracellular matrix remodeling in the airways of asthmatic patients. It is unclear whether this process is affected by antiasthma therapies. Here, we evaluated whether a glucocorticoid, budesonide (BUD), and a long-acting beta 2-agonist, formoterol (FM), either alone or in combination, modified BK-induced lung fibroblast differentiation, and affected the BK-activated intracellular signaling pathways. Methods. Human fetal lung fibroblasts were incubated with BUD (0.001-0.1 mu M) and/or FM (0.0001-0.1 mu M) before exposure to BK (0.1 or 1 mu M). Fibroblast differentiation into alpha-smooth-muscleactin-positive (alpha-SMA(+)) myofibroblasts, BK2 receptor (B2R) expression, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation (p-ERK1/2), intracellular Ca2+ concentration ([Ca2+](i)), and p65 nuclear factor kappa B translocation were evaluated. Results. BUD (0.1 mu M) and FM (0.1 mu M), either alone or in combination, completely inhibited BK-induced alpha-SMA protein expression and decreased the numbers of alpha-SMA(+) fibroblasts, with a clear reduction in alpha-SMA stress fibers organization. BUD also completely inhibited the increase of B2R, whereas FM with or without BUD had no effect. BK-induced increases of [Ca2+](i) and p-ERK1/2 were significantly reduced to similar levels by BUD and FM, either alone or in combination, whereas p65 translocation was completely inhibited by all treatments. Conclusion. Both BUD and FM, either alone or in combination, effectively inhibited the BK-induced differentiation of fibroblasts into alpha-SMA(+) myofibroblasts and the intracellular signaling pathways involved in fibroblast activation. These results suggest that BUD and FM combination therapy has potential to inhibit fibroblast-dependent matrix remodeling in the airways of asthmatic patients.