A new era in the treatment of progressive fibrosing interstitial lung diseases

Abstract

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by an irreversible progression of pulmonary fibrosis and functional lung decline. Current antifibrotic therapies (nintedanib and pirfenidone for IPF and nintedanib for PPF) can reduce disease progression but not halt or reverse it. PPF and IPF share common pathophysiological pathways that need to be further elucidated for the development of novel therapeutic strategies. The educational aim of this review is to explain the pathogenic pathways that have led to the discovery of new therapeutic agents and their favourable implementation in phase 2 and 3 studies. This includes phosphodiesterase 4 inhibitors, αvβ6 and αvβ1 integrin inhibitors, lymphosphatidic acid antagonists, inhaled treprostinil, hedgehog inhibitors, tyrosine kinase inhibitors and angiotensin type 2 receptor agonists. The aim is also to better understand current therapeutic challenges and future perspectives, including cellular therapies, exosomes and their cargoes, as well as the integration of transcriptomics and proteomics, plus gene therapy.

FIGURE 1

Specific molecular pathways involved in the pathogenesis of fibrosis and novel therapeutic targets. AT₁R: angiotensin type 1 receptor; cAMP: cyclic adenosine monophosphate; CTGF: connective tissue growth factor; ECM: extracellular matrix; FGFR: fibroblast growth factor receptor; LPA1: lymphosphatidic acid 1; PDE4: phosphodiesterase 4; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; TGF-β: transforming growth factor β; VEGFR: vascular endothelial growth factor receptor. Figure created with BioRender.com.