Insights into the Cellular and Molecular Mechanisms behind the Antifibrotic 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. This study examined the antifibrotic properties of nerandomilast, a preferential phosphodiesterase 4B inhibitor, focusing on its effects on myofibroblasts (MFs) and endothelial cells. Using cytokine-stimulated human IPF lung fibroblasts and RNA sequencing, we assessed the effects of nerandomilast on MF contractility, MF markers, and differentiation mechanisms. In addition, using human microvascular endothelial cells, we assessed endothelial barrier integrity and monocyte adhesion in a three-dimensional microfluidic chip. Our results show that nerandomilast significantly inhibited MF contractility and marker expression in cytokine-stimulated human IPF lung fibroblast cells. Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor signaling events while inhibiting mitogen-activated protein kinase signaling pathways and transforming growth factor β signaling. Nerandomilast also significantly reduced microvascular permeability in cytokine-stimulated human lung microvascular endothelial cells. Finally, in an adeno-associated virus-human diphtheria toxin receptor/diphtheria toxin mouse model of acute lung injury, nerandomilast significantly inhibited total protein in lavage, total macrophages, neutrophils, cell count, and VCAM-1 expression. In summary, our results demonstrate that nerandomilast induces the dedifferentiation of human IPF lung MFs and diminishes their contractility <i>in vitro</i> by interfering with transforming growth factor β, mitogen-activated protein kinase phosphatase-1, and G-protein-coupled receptor signaling pathways. It also mitigates vascular dysfunction by strengthening endothelial junctions and inhibiting adhesion protein expression. These findings highlight nerandomilast's potential therapeutic use in IPF by providing insights into its cellular and molecular actions.