Lung Fibroblast Proteoglycan Production Induced by Serum Is Inhibited by Budesonide and Formoterol

Abstract

Proteoglycans contribute to extracellular matrix remodeling in asthmatic airways. We investigated the effects of budesonide, a glucocorticoid, and formoterol, a long-acting beta2-adrenergic agonist, on serum-induced proteoglycan production by human lung fibroblasts. In 10% serum, total proteoglycan production was increased 1.5-fold (P < 0.01) compared with basal production in 0.4% serum. Budesonide (10(-8) M) reduced this increase by 44% (P < 0.01) and, whereas formoterol (10(-10)-10(-8) M) had no inhibitory effects, the drug combination abolished the increase (P < 0.01) without affecting fibroblast proliferation. This synergistic effect required functional glucocorticoid and beta-adrenergic receptors. The production of the proteoglycans decorin, biglycan, perlecan, and versican was increased 2.5- to 5-fold (P < 0.01) in 10% serum. Combination treatment with budesonide (10(-8) M) and formoterol (10(-10) M) abolished this increase to a significantly greater extent than either drug alone. In 10% serum, only versican mRNA was increased 1.4-fold (P < 0.05), whereas decorin mRNA was reduced to 39% (P < 0.01) of basal expression. These serum effects were counteracted by the drug combination, but there were no significant differences between the combination and either drug alone. Thus, the budesonide and formoterol combination seems to synergistically control serum-induced proteoglycan production, primarily at the post-transcriptional level. In conclusion, the proteoglycan upregulation characteristic of asthmatic airways may be limited by combination therapy with budesonide and formoterol.

Differences in proteoglycan deposition in the airways of moderate and severe asthmatics

“…While steroids could potentially affect PG deposition [26], there is no a priori reason to expect that steroids would differentially affect deposition in the subepithelial versus smooth muscle layer.…”

Clinical relevance of airway remodelling in airway diseases

“…JAMES AND S. WENZEL I, III and IV [51][52][53][54]; decorin [55,56]; laminin [57,58]; tenascin [53,59,60]; versican [55,56,59]; biglycan [56,59,61]; perlecan [56,61]; hyaluranon [50,62]; and decreased lumican [55]. Reductions in elastin have been observed in a number of studies [63][64][65].…”

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β2-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

“…Likewise, dilutions of LABA plus glucocorticoid in fixed ratios resulted in clear enhancements in RGS2 expression with FP or budesonide concentrations in the 0.1-1.0 nM range and LABA concentrations of 0.1 nM for salmeterol and 10 pM for formoterol. In the context of inhaled therapeutics, lung concentrations of ICS can readily reach 1-100 nM (Esmailpour et al, 1997;Miller-Larsson and Selroos, 2002;Todorova et al, 2006;van den Brink et al, 2008). Furthermore, in mild atopic asthmatics, inhalation of a moderate dose of budesonide (800 mg per day) for 10 days significantly increased the expression of glucocorticoid-induced leucine zipper (GILZ/ TSC22D3) and FK506-binding protein 51 (FKBP51/FKBP5) (Kelly et al, 2012).…”