Pharmacological Modulation of the Bradykinin-Induced Differentiation of Human Lung Fibroblasts: Effects of Budesonide and Formoterol

Abstract

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.

Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective β2-adrenoceptor agonists and dexamethasone

“…This effect was synergistically enhanced when dexamethasone was added to those tested β-agonists. Concordant with our finding, some studies have shown that the transformation of fibroblasts into myofibroblasts decreases in the human lung when glucocorticoids are combined with β 2 -agonists (Baouz et al, 2005;Kelly et al, 2010;Sabatini et al, 2012), and thus, both drugs limit transformation into myofibroblasts in asthmatic/RAO airways.…”

Bradykinin B2 receptor expression in the bronchial mucosa of allergic asthmatics: the role of NF‐kB

“…In parallel, the current study observed an overexpression of both total and nuclear NF‐kB in the bronchial mucosa of asthmatics after allergen challenge, and a modulation of bradykinin‐ and Th2 cytokines‐induced B2R expression by the NF‐kB inhibitor in primary bronchial fibroblasts. Bradykinin and IGF‐1 are known to activate NF‐kB in conjunction with (myo)fibroblast differentiation in HFL‐1 cells and, of note, in human osteoblastic cell line and gingival fibroblasts NF‐kB, together with p38 MAPK, is involved in B2R expression. The corticosteroid budesonide can suppress bradykinin‐induced up‐regulation of B2R expression, and bradykinin‐induced αSMA + fibroblasts and NF‐kB nuclear translocation in human fetal lung fibroblasts .…”

Link between vitamin D and airway remodeling

“…Budesonide and formoterol, both alone or in combination, were shown to effectively inhibit bradykinin-induced differentiation of fibroblasts into myofibroblasts and to have the potential to inhibit fibroblast-dependent matrix remodeling in the airways of asthmatic patients. However, there was no consistent evidence of an inhibitory effect of steroids on remodeling 49. Arachidonic acid-derived mediators, ie, cysteinyl leukotrienes and prostaglandins, production of which is decreased by vitamin D, constitute a potential target for modulation of remodeling 40.…”