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

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

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Article number607689
JournalFrontiers in Pharmacology
Volume11
DOIs
Publication statusPublished - 2020 Dec 11

Bibliographical note

Funding Information:
This work was supported through grants from the National Institute of Allergy and Infectious Diseases (NIAID 2P01AI062885 (AB), NCATS UL1TR002373 (AB)), Falk Q24 Catalyst Award (AB and SH), and the National Science Foundation (NSF DMR-1808251 (SH)).

Publisher Copyright:
© Copyright © 2020 Skibba, Drelich, Poellmann, Hong and Brasier.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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