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

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.

Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

“…In COVID-19 patients, radiographic evidence of a wide range of pulmonary alterations associated to fibrotic damage and lung functional impairment are commonly observed (Shi et al, 2020). In fatal cases, increased expression of ECM-specific proteins and ECM regulators has been reported (Skibba et al, 2020). These data suggest that lung fibrosis onset is a pathogenic mechanism of severe SARS-CoV-2 infections.…”

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

“…To investigate the mechanism involved in the development of PF in vivo , we examined the expression of the classic EMT-related markers, E-cadherin, N-cadherin and Vimentin, in the lung tissues of mice. EMT, the transition from an epithelial to a mesenchymal state, is one of the crucial processes in PF ( Yang et al, 2019 ; Skibba et al, 2020 ). BLM induced the development of EMT in WT mice, which was associated with significant downregulation of the protein expression of the epithelial cell marker E-cadherin, and the upregulation of the protein level of the mesenchymal cell markers, N-cadherin and Vimentin.…”

The oncogenic landscape of the idiopathic pulmonary fibrosis: a narrative review

“…Growing evidence indicates that the changes in ECM composition and mechanical properties which characterize IPF can be exploited for therapeutic purposes. Synthetic materials as polyacrylamide, hydrogels, highly crosslinked polymer networks as well as liposomes, polymeric nanoparticles represent engineered platforms which can be decorated with cell-adhesive ligands, signalling factors, drugs which can modulate lung remodelling (270)(271)(272).…”