Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 27, 2021
- Source ID
- 10.1038/s41467-021-24853-8
Entities
People
- Bradford J Smith
- Chelsea M. Magin
- David A Schwartz
- Duncan Davis-Hall
- Evgenia Dobrinskikh
- Hong Wei Chu
- Ian T. Stancil
- Ivana V. Yang
- Jacob E. Michalski
- Jin-Ah Park
Organizations
- National Heart, Lung, and Blood Institute
- National Institute of Environmental Health Sciences
- National Institute on Aging
- National Science Foundation
- United States Army
- United States Department of Defense
- United States Department of Health and Human Services