Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nat Commun. 2021 Jul 27;12(1):4566. doi: 10.1038/s41467-021-24853-8.

Abstract

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Amphiregulin / genetics
  • Amphiregulin / metabolism
  • Biophysical Phenomena / drug effects
  • Epithelium / drug effects
  • Epithelium / physiopathology*
  • ErbB Receptors / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Genetic Predisposition to Disease
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / physiopathology*
  • Keratin-5 / genetics
  • Keratin-5 / metabolism
  • Lung / drug effects
  • Lung / physiopathology*
  • Mucin-5B / genetics
  • Mucin-5B / metabolism
  • Quinazolines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Risk Factors
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • Tyrphostins / pharmacology
  • Verteporfin / pharmacology
  • YAP-Signaling Proteins

Substances

  • AREG protein, human
  • Adaptor Proteins, Signal Transducing
  • Amphiregulin
  • Keratin-5
  • Mucin-5B
  • Quinazolines
  • RNA, Messenger
  • Transcription Factors
  • Tyrphostins
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Verteporfin
  • RTKI cpd
  • ErbB Receptors