Epithelia from Small Airways and Honeycomb Cysts Are Dynamically and Structurally Similar in Idiopathic Pulmonary Fibrosis
Year: 2021
Type: conference-abstract
Abstract: Rationale: Distal airspace remodeling in idiopathic pulmonary fibrosis (IPF) includes the formation of microscopic honeycomb cysts (HCs) lined by a pseudostratified, mucociliary epithelium with features similar to that of the distal airway. While these HCs share many characteristics with the IPF small airway, the etiology of these bronchiolized, cystic regions remains unclear. The purpose of the work was aimed at understanding the dynamic and structural characteristics of airway and HC epithelia in the IPF lung. Methods: Primary human airway epithelial cells were obtained from explanted IPF lungs (n = 5 donors). Epithelial cells isolated from different regions (large airways, small airways, HCs) were cultured at air-liquid interface (ALI) for 28 days until mature, fully-differentiated epithelia were achieved. Cell speed was assessed using time-lapse microscopy and quantified using particle image velocimetry. Images of F-actin labeled cell boundaries were segmented and analyzed to measure the cell shape index (q, Perimeter / Area) and aspect ratio (AR). Differences in cell types were determined via immunofluorescent staining for various markers: KRT5 and KRT17 for basal cells, MUC5B and MUC5AC for secretory cells, and Ac--tubulin for ciliated cells. Results: Airway epithelia from IPF large airways transitioned from an unjammed (migratory) to jammed (non-migratory) state around ALI day 8, whereas small airway and HC epithelia persisted in an unjammed state until approximately day 28. Cell shape analysis demonstrated a change from an elongated morphology into a hexagonal, "cobblestone" epithelial morphology in large airway cultures across this jamming transition, whereas small airway and HC cultures maintained an elongated cell phenotype until day 28. Cell type marker staining revealed a significant increase in both KRT5-positive and KRT17-positive basal cells and MUC5B-positive secretory cells in both small airway and HC epithelia compared to large airways. Conclusion: These results indicate that there is a regionally-specific biophysical signature in IPF small airway and HC epithelia characterized by a temporal and structural prolongation of the jamming transition leading to a chronic migratory phenotype. Additionally, small airway and HC epithelia share characteristic cell-type changes suggesting these populations possibly share a common origin. Taken together, these data support the hypothesis that the small airways are a significant component of IPF pathobiology and may directly contribute to the formation of honeycomb cysts through persistent activation of this migratory phenotype.
Institution: University of Colorado Anschutz
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4240391640