Kistemaker Loes E M, Oenema Tjitske A, Baarsma Hoeke A, Bos I Sophie T, Schmidt Martina, Facchinetti Fabrizio, Civelli Maurizio, Villetti Gino, Gosens Reinoud
Department of Molecular Pharmacology, University of Groningen, The Netherlands;
Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Am J Physiol Lung Cell Mol Physiol. 2017 Sep 1;313(3):L507-L515. doi: 10.1152/ajplung.00069.2017. Epub 2017 Jun 8.
Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β-induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction.
磷酸二酯酶4（PDE4）抑制剂与抗胆碱能药物联合治疗可诱导慢性阻塞性肺疾病（COPD）的支气管保护作用。支气管收缩过程中产生的机械力可能导致气道重塑。因此，我们研究了PDE4抑制剂和抗胆碱能药物对支气管收缩诱导的重塑的影响。由于PDE4抑制剂和抗胆碱能药物的作用机制不同，我们推测这两类药物存在功能相互作用。将豚鼠精密肺切片先用PDE4抑制剂CHF-6001或罗氟司特和/或抗胆碱能药物噻托溴铵或格隆溴铵预孵育，然后用乙酰甲胆碱（10μM）或转化生长因子-β（TGF-β，2ng/ml）刺激48小时。研究了对气道平滑肌重塑、气道收缩和TGF-β释放的抑制作用。CHF-6001（0.3-100 nM）可完全抑制乙酰甲胆碱诱导的平滑肌肌球蛋白蛋白表达，而罗氟司特（1μM）的作用较小。噻托溴铵和格隆溴铵可完全抑制乙酰甲胆碱诱导的气道重塑（0.1-30 nM）。CHF-6001与噻托溴铵或格隆溴铵联合使用，在单独使用时部分有效浓度下，可完全抑制乙酰甲胆碱诱导的联合重塑。CHF-6001不影响气道关闭，对TGF-β诱导的重塑作用有限，但它可抑制乙酰甲胆碱诱导的TGF-β释放。PDE4抑制剂CHF-6001以及程度较轻的罗氟司特，与长效抗胆碱能药物（LAMA）噻托溴铵和格隆溴铵可抑制支气管收缩诱导的重塑。CHF-6001与抗胆碱能药物联合使用比单独使用各化合物更有效。这种协同作用可能是由于抑制TGF-β释放和支气管收缩的作用机制不同所致。
