PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells

• Published in: British journal of pharmacology Vol. 181; no. 23; pp. 4766 - 4781
• Main Authors: Reininger, Dennis, Fundel‐Clemens, Katrin, Mayr, Christoph H., Wollin, Lutz, Laemmle, Baerbel, Quast, Karsten, Nickolaus, Peter, Herrmann, Franziska Elena
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-12-2024
• Subjects: Animal models; BI 1015550; Bleomycin; cAMP; Cell culture; Computed tomography; cyclic nucleotide phosphodiesterases, type 4; Disease; Endothelial cells; Epithelial cells; Fibrosis; idiopathic pulmonary fibrosis; Inflammatory diseases; interstitial lung disease; Lung diseases; MMP‐7; Molecular modelling; nerandomilast; Phosphodiesterase; phosphodiesterase‐4B inhibitors; Pulmonary fibrosis; Respiratory function; Signal transduction; Transcriptomes; MMP‐7; phosphodiesterase‐4B inhibitors; interstitial lung disease; BI 1015550; cyclic nucleotide phosphodiesterases, type 4; idiopathic pulmonary fibrosis; cAMP; nerandomilast
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.17303

Background and Purpose
The PDE4 family is considered a prime target for therapeutic intervention in several fibro‐inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor.
Experimental Approach
In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high‐resolution computed tomography scan/AI‐Ashcroft score), whole‐lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next‐generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter‐regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease‐relevant in vitro assay of IPF.
Key Results
Nerandomilast improved the decline of lung function parameters in bleomycin‐treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single‐cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease‐related (bio)markers were inhibited by nerandomilast in a concentration‐dependent manner.
Conclusions and Implications
This study further supports the available knowledge about the anti‐inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis.