Insights Into the Cellular and Molecular Mechanisms Behind the Antifibrotic Effects of Nerandomilast.

Abstract

The quest for innovative pharmacologic interventions in idiopathic pulmonary fibrosis (IPF) is a challenging journey. The complexity of the disease demands a comprehensive approach targeting multiple cell types and pathways. This study examined the antifibrotic properties of nerandomilast, a preferential phosphodiesterase 4B inhibitor, focusing on its effects on myofibroblasts (MF)s and endothelial cells. Using cytokine-stimulated human IPF lung fibroblasts (IPF-HLF) and RNA-seq, we assessed the effect nerandomilast has on MF contractility, MF markers and differentiation mechanisms. In addition, using human microvascular endothelial cells, endothelial barrier integrity and monocyte adhesion were assessed in a 3D microfluidic chip. Our results show that nerandomilast significantly inhibited MF contractility and marker expression in cytokine-stimulated IPF-HLF cells. Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor (GPCR) signaling events while inhibiting mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta (TGFβ) 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 in vitro by interfering with TGFβ, MAPK phosphatase-1 and GPCR 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).