Background: Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease characterized by chronic bronchitis,  emphysema, small airway obstruction, impaired lung repair, and remodeling, all of which lead to a  decline in lung function. Cigarette smoke (CS) is a major risk factor for COPD, inducing prolonged lung and systemic inflammation. At present, we lack effective pharmacological treatments to slow lung function decline.

Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor, improves lung function and exacerbations in COPD. However, the systemic side effects limit its use as a treatment. In this regard, Tanimilast, a novel inhaled PDE4 inhibitor, allows the direct targeting of the lung with reduced systemic exposure.

Aim: Here we used a combined treatment of Tanimilast with Formoterol (long-acting beta-agonists) to investigate the effect on lung epithelial progenitor cell function. For this, we used an in vitro approach of lung organoids with and without CS-extract (CSE) exposure..

Results: The organoid assay revealed a limited effect on organoid growth after Formoterol treatment alone. In contrast, Tanimilast treatment increased organoid number, with even larger effects observed when added concomitantly with Formoterol. Organoid growth was considerably disrupted in response to CSE exposure, however, combined treatment with Tanimilast and Formoterol boosted organoid growth in CSE-pretreated organoids.

Conclusion: Our findings support the beneficial effect of combined Tanimilast-Formoterol therapy on rescuing CS-impaired organoid formation, suggesting this to be a promising therapeutic approach for defective lung repair in COPD.