Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
Br J Pharmacol. 2017 Nov;174(21):3848-3864. doi: 10.1111/bph.13982. Epub 2017 Sep 20.
Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of β -adrenoceptors (β -AR) has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of β -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting β -adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis.
We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with IPF (IPF-LF). The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-β1.
In both HLF and IPF-LF, olodaterol attenuated TGF-β-induced expression of α-smooth muscle actin, fibronectin and endothelin-1 (ET-1), FGF- and PDGF-induced motility and proliferation and TGF-β/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators (TGF-ß, MMP-9 and tissue inhibitor of metalloproteinase-1). Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-β-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression.
Olodaterol showed anti-fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis.
特发性肺纤维化（IPF）是一种致命的呼吸系统疾病，其特征是成纤维细胞过度激活，最终导致肺部瘢痕形成。虽然β-肾上腺素能受体（β-AR）的激活已被证明可抑制主要在细胞系中发生的促纤维化事件，但β-肾上腺素受体激动剂的作用尚未得到充分表征。本研究的目的是探讨长效β-肾上腺素受体激动剂奥洛达特罗在原代人肺成纤维细胞（HLF）和肺纤维化的小鼠模型中的抗纤维化活性。
我们评估了奥洛达特罗抑制不同促纤维化介质诱导的原代 HLF 中各种促纤维化机制的活性，这些原代 HLF 来自对照供体和特发性肺纤维化（IPF-LF）患者。奥洛达特罗通过吸入每天一次的方式，在博来霉素或 TGF-β1 过表达诱导的肺纤维化的小鼠模型中进行预防或治疗，探索其体内抗纤维化活性。
在 HLF 和 IPF-LF 中，奥洛达特罗均可减弱 TGF-β诱导的α-平滑肌肌动蛋白、纤维连接蛋白和内皮素-1（ET-1）、FGF 和 PDGF 诱导的运动和增殖以及 TGF-β/ET-1 诱导的收缩。体内奥洛达特罗显著减弱博来霉素诱导的肺重量增加，减少支气管肺泡灌洗细胞计数，并抑制促纤维化介质（TGF-β、MMP-9 和金属蛋白酶组织抑制剂-1）的释放。仅在预防治疗方案中才增加用力肺活量。在 TGF-β过表达模型中，奥洛达特罗还降低了 Col3A1 mRNA 表达。
奥洛达特罗在来自对照和 IPF 患者的原代 HLF 以及肺纤维化的小鼠模型中表现出抗纤维化特性。
