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

Federica Sabatini, Loredana Petecchia, Cesare Usai, Michela Silvestri, Giovanni A. Rossi, Anna Miller-Larsson, Fabio L M Ricciardolo

Research output: Contribution to journalArticle

Abstract

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 β2-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 μM) and/or FM (0.0001-0.1 μM) before exposure to BK (0.1 or 1 μM). Fibroblast differentiation into α-smooth-muscle-actin-positive (α-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 μM) and FM (0.1 μM), either alone or in combination, completely inhibited BK-induced α-SMA protein expression and decreased the numbers of α-SMA+ fibroblasts, with a clear reduction in α-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 α-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.

Original languageEnglish
Pages (from-to)1004-1011
Number of pages8
JournalJournal of Asthma
Volume49
Issue number10
DOIs
Publication statusPublished - Dec 2012

Keywords

  • α-smooth muscle actin (α-SMA)
  • Bradykinin B2 receptor (B2R)
  • Human lung fibroblasts
  • Mitogen-activated protein kinases (MAPKs)

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Immunology and Allergy
  • Pediatrics, Perinatology, and Child Health

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