D29-24 Nerandomilast Attenuates Pulmonary Fibrosis by Promoting Alveolar Epithelial Cell Differentiation

Rationale The PDE4B inhibitor Nerandomilast is a novel therapeutic candidate for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), but its anti-fibrotic mechanisms remain incompletely understood. Alveolar epithelial type II (AT2) cells serve as progenitors for alveolar repair, and impaired AT2 differentiation contributes to the progression of pulmonary fibrosis. We investigated the effects of Nerandomilast on alveolar epithelial cell dynamics. Methods Pulmonary fibrosis was induced in C57BL/6 mice by intratracheal bleomycin (BLM) administration. Nerandomilast (12.5 mg/kg, orally) or vehicle was administered starting daily 7 days after BLM, and lungs were analyzed on days 0, 7, 10, 14, and 21. Fibrosis severity was assessed by lung hydroxyproline content and histological scoring. AT2 cell fate was analyzed using lineage tracing, multicolor flow cytometry, and immunofluorescence staining. Results Nerandomilast treatment significantly attenuated BLM-induced pulmonary fibrosis on day 21, as evidenced by reduced hydroxyproline content and lower histological fibrosis scores compared to vehicle controls. Lineage-tracing analysis using Sftpc-CreER;RCL-ZsGreen mice showed a decrease in AT2 cells on day 7 and an increase in KRT8+ transitional epithelial cells on day 10 after BLM exposure. In the Nerandomilast-treated group, differentiation into KRT8+ epithelial cells was reduced, whereas differentiation into AT1 (PDPN+) cells was enhanced. Conclusions Nerandomilast facilitates AT2-to-AT1 differentiation, leading to enhanced alveolar repair and attenuation of pulmonary fibrosis. These findings support its potential as a therapeutic agent for IPF and PPF.