In:
British Journal of Pharmacology, Wiley, Vol. 174, No. 21 ( 2017-11), p. 3848-3864
Abstract:
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 2 ‐adrenoceptors (β 2 ‐AR) has been shown to inhibit pro‐fibrotic events primarily in cell lines, the role of β 2 ‐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 2 ‐adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis. Experimental Approach 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. Key Results 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. Conclusion and Implications Olodaterol showed anti‐fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2029728-2
SSG:
15,3
