Abstract
Background: The long-acting β2-agonist (LABA) olodaterol was shown to have anti-fibrotic activity in primary human lung fibroblasts (Herrmann et al, Eur Respir J. 2014;44:Suppl.58) however, its anti-fibrotic in vivo efficacy has not yet been demonstrated.
Aim: To test the effect of olodaterol in a mouse model of bleomycin induced lung fibrosis.
Methods: Bleomycin at a dose of 0.5 mg/kg (1.5-2 U/mg) was intratracheally instilled in C57BL/6 mice on day 0. In a preventive (day 1-20) or therapeutic (day 7 -20) treatment regimen mice were exposed once daily for 5 min to an aqueous solution of olodaterol (1 mg/mL) aerosolized with a jet nebulizer. At the end of the study (day 21) lung density was assessed by micro CT analysis and lung function was measured with a FlexiVent system. Bronchoalveolar lavage fluid (BALF) was analyzed for total and differential cell counts and pro-fibrotic cytokines.
Results: The bleomycin challenge induced an increase in lung tissue density, white blood cell (WBC) count and protein concentration in the BAL fluid and a decrease in forced vital capacity (FVC). In the preventive treatment regimen olodaterol attenuated tissue density by 45%, WBC count by 31%, protein by 63% and FVC by 57%. Pro-fibrotic cytokines like TGF-ß or MMP-9 were diminished by 57% and 48%, respectively. Therapeutic treatment with olodaterol attenuated the increase in lung density and the decrease in FVC by 10% and 18%, respectively. WBC accumulation was attenuated by 25% and the increase in total protein, TGF-ß and MMP-9 levels in BALF was inhibited by 43%, 58% and 49%, respectively.
Conclusion: At doses of maximal bronchodilation, olodaterol showed anti-fibrotic properties in a mouse model of bleomycin induced lung fibrosis.
- Copyright ©the authors 2016
