Insights into the Cellular and Molecular Mode of Action behind the Anti-Fibrotic Effects of Nerandomilast

The quest for innovative pharmacologic interventions in idiopathic pulmonary fibrosis (IPF) is a challenging journey. The complexity of the disease demands a comprehensive approach that targets multiple cell types and pathways. In this study, we explored the anti-fibrotic properties of nerandomilast, a preferential phosphodiesterase 4B inhibitor, focusing on its effects on myofibroblasts (MFs) and endothelial cells. Our findings demonstrate that nerandomilast induces the dedifferentiation of human lung MFs and diminishes their contractility in vitro by interfering with TGFβ and GPCR signaling pathways. Moreover, nerandomilast effectively mitigates features of vascular dysfunction, such as increased vascular permeability and immune cell infiltration, both in vitro and in vivo. This is accomplished by strengthening endothelial junctions and inhibiting the expression of adhesion molecule proteins. Furthermore, in a rat model of bleomycin-induced pulmonary fibrosis, nerandomilast normalizes the specialization of endothelial cell types. The results of this study significantly contribute to the growing knowledge around the potential therapeutic use of nerandomilast in the treatment of IPF by providing valuable insights into its cellular and molecular mode of action