Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis.

Melissa Skibba,Adam Drelich,Allan R Brasier,Michael Poellmann,Seungpyo Hong

doi:10.3389/fphar.2020.607689

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2–3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.

Highlights

The Interstitial Lung Diseases (ILDs) are a heterogeneous group of parenchymal diseases with various mixtures of fibrosis and inflammation
We propose that nanomedicine can advance the therapeutics of Idiopathic Pulmonary Fibrosis (IPF) by enhancing therapeutic efficacy and reducing systemic effects, thereby facilitating the development of the generation of therapeutics for pulmonary fibrosis treatment
Myofibroblasts are principal components of extracellular matrix (ECM) production that result in airspace loss and mortality

Summary

INTRODUCTION

The Interstitial Lung Diseases (ILDs) are a heterogeneous group of parenchymal diseases with various mixtures of fibrosis and inflammation. NFκB -dependent activation of the core EMT regulators results in expression of COL and FN, key ECM regulators of myofibroblast expansion, airway remodeling and expansion of the subepithelial basement membrane Supporting this chromatin remodeling mechanism, recent analyses using transposase-accessible- generation sequencing (ATAC-Seq) in highly differentiated lower airway epithelial cells infected with Respiratory Syncytial Virus demonstrate that the TGFβ-FN-JUN pathways controlling EMT are activated by chromatin decondensation at their proximal promoters (Xu et al, 2020). These fundamental studies of the NFκB -BRD4 pathway were initially developed in vitro, evidence that NFκB mediates mesenchymal transition, myofibroblast expansion, and pulmonary fibrosis has been developed in in vivo (Tian et al, 2016).

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CONCLUSION