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In asthma, basic fibroblast growth factor (FGF-2) plays an important (patho)physiological role. This study examines the effects of FGF-2 on the transforming growth factor-ß (TGF-ß)-stimulated differen- tiation of airway smooth muscle (ASM) cells in vitro. The differenti- ationofhumanASM cellsafterincubationwith TGF-ß (100 pM) and/ or FGF-2 (300 pM) for48 hourswas assessed by increases in contrac- tile protein expression, actin-cytoskeleton reorganization, enhance- ments in cell stiffness, and collagen remodeling. FGF-2 inhibited TGF-ß-stimulated increases in transgelin (SM22) and calponin gene expression (n = 15, P < 0.01) in an extracellular signal-regulated kinase 1/2 (ERK1/2) signal transduction-dependent manner. The abundance of ordered a-smooth muscle actin (a-SMA) filaments formed in the presence of TGF-ß were also reduced by FGF-2, as was the ratio of F-actin to G-actin (n = 8, P < 0.01). Furthermore, FGF-2 attenuated TGF-ß-stimulated increases in ASM cell stiffness and theASM-mediated contractionoflattices, composed ofcollagen fibrils (n = 5, P < 0.01). However, the TGF-ß-stimulated production ofIL-6was notinfluenced by FGF-2 (n = 4, P> 0.05), suggesting that FGF-2antagonism is selectiveforthe regulation ofASM cell contrac- tile protein expression, organization, and function. Another mito- gen, thrombin (0.3 U ml^sup -1^), exerted no effect on TGF-ß-regulated contractile protein expression (n = 8, P > 0.05), a-SMA organization, or the ratio of F-actin to G-actin (n = 4, P > 0.05), suggesting that the inhibitory effect of FGF-2 is dissociated from its mitogenic actions. The addition of FGF-2, 24 hours afterTGF-ß treatment, still reduced contractile protein expression, even when the TGF-ß-receptor ki- nase inhibitor, SB431542 (10 mM), was added 1 hour before FGF-2. We conclude that the ASM cell differentiation promoted by TGF-ß is antagonized by FGF-2. A better understanding ofthe mechanism of action for FGF-2 is necessary to develop a strategy for therapeutic exploitation in the treatment of asthma.
Keywords: airway wall remodeling; a-smooth muscle actin; asthma; cytoskeleton; transgelin
Airway wall remodeling (AWR) contributes to airway dysfunction in asthma. AWR comprises an array of persistent tissue structural changes that are thought to occur through a process of injury and dysregulated repair, linked to chronic airway inflammation. Fea- tures of AWR include the increased deposition of extracellular matrix (ECM), airway smooth muscle (ASM) hyperplasia and hypertrophy, mucous cell metaplasia, and angiogenesis (1). The deposition of collagens I and III in the...