Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Italy.
Br J Pharmacol. 2013 Jan;168(1):266-75. doi: 10.1111/j.1476-5381.2012.02180.x.
An important objective in asthma therapy is to prevent the accelerated growth of airway smooth muscle cells which leads to hyperplasia and bronchial hyperreactivity. We investigated the effect of combination of salbutamol and PPARγ agonists on growth factor-stimulated human bronchial smooth muscle cell (BSMC) proliferation.
Synergism was quantified by the combination index-isobologram method. Assays used here included analyses of growth inhibition, cell viability, DNA fragmentation, gene transcription, cell cycle and protein expression.
The PPARγ gene was highly expressed in BSMC and the protein was identified in cell nuclei. Single-agent salbutamol or PPARγ agonists prevented growth factor-induced human BSMC proliferation within a micromolar range of concentrations through their specific receptor subtypes. Sub-micromolar levels of combined salbutamol-PPARγ agonist inhibited growth by 50% at concentrations from ∼2 to 12-fold lower than those required for each drug alone, without induction of apoptosis or necrosis. Combination treatments also promoted cell cycle arrest at the G1/S transition phase and inhibition of ERK phosphorylation.
The synergistic interaction between PPARγ agonists and β(2) -adrenoceptor agonists on airway smooth muscle cell proliferation highlights the anti-remodelling potential of this combination in chronic lung diseases.
哮喘治疗的一个重要目标是防止气道平滑肌细胞的快速生长，这会导致细胞增生和支气管高反应性。我们研究了沙丁胺醇和过氧化物酶体增殖物激活受体 γ（PPARγ）激动剂联合对生长因子刺激的人支气管平滑肌细胞（BSMC）增殖的影响。
通过组合指数-等效应线图方法来量化协同作用。这里使用的测定方法包括生长抑制分析、细胞活力分析、DNA 片段化分析、基因转录分析、细胞周期分析和蛋白质表达分析。
PPARγ 基因在 BSMC 中高表达，其蛋白存在于细胞核中。单一用药沙丁胺醇或 PPARγ 激动剂通过其特定的受体亚型，在微摩尔浓度范围内预防生长因子诱导的人 BSMC 增殖。亚微摩尔浓度的联合沙丁胺醇-PPARγ 激动剂抑制生长的 50%所需浓度比单独用药低 2 到 12 倍，而不会诱导细胞凋亡或坏死。联合治疗还促进细胞周期停滞在 G1/S 转换期，并抑制 ERK 磷酸化。
PPARγ 激动剂和β2-肾上腺素能受体激动剂在气道平滑肌细胞增殖方面的协同作用，突出了这种联合在慢性肺部疾病中的抗重塑潜力。
