Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Br J Pharmacol. 2024 Dec;181(23):4766-4781. doi: 10.1111/bph.17303. Epub 2024 Aug 25.
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.
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.
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.
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.
磷酸二酯酶 4（PDE4）家族被认为是几种纤维炎症性疾病治疗干预的主要靶点。我们研究了尼拉米司特（BI 1015550），一种选择性 PDE4B 抑制剂的分子机制。
除了特发性肺纤维化（IPF；肺功能测量/高分辨率计算机断层扫描/AI-Ashcroft 评分）的临床相关参数外，还通过下一代测序（NGS）分析了治疗性雄性 Wistar 肺纤维化大鼠模型的全肺匀浆。将数据与源自人类 IPF 样本的公共领域数据进行匹配，以研究大鼠模型对人类 IPF 的反映程度。我们对人类单细胞中尼拉米司特治疗后反调控基因进行评分，并使用与人类相关的 IPF 体外检测验证在大鼠模型中发现的疾病标志物。
尼拉米司特改善了博来霉素处理动物肺功能参数的下降。在 NGS 研究中，尼拉米司特治疗可使大多数由博来霉素处理引起的转录本失调控得到正常化。最值得注意的是，在动物模型中也发现了大量在人类 IPF 疾病中被鉴定为失调的转录本，并且这些转录本被尼拉米司特逆转。映射到单细胞数据显示对间充质、上皮和内皮细胞群的影响最强。在原代人上皮细胞培养系统中，尼拉米司特以浓度依赖性方式抑制几种与疾病相关的（生物）标志物。
本研究进一步支持了尼拉米司特的抗炎/抗纤维化机制的现有知识，并提供了有关尼拉米司特治疗肺纤维化影响的作用模式和信号通路的新见解。
