The Idiopathic Pulmonary Fibrosis Honeycomb Cyst Contains A Mucocilary Pseudostratified Epithelium

Abstract

BackgroundWe previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP.MethodsImmunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC).ResultsMUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC.ConclusionsThe distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway.

Airway Progenitor Clone Formation Is Enhanced by Y-27632–Dependent Changes in the Transcriptome

“…Beyond the positive effects of Y-27632 treatment on clone formation, our study also suggests that clone formation in the absence of Y-27632 is mediated by nasal airway basal progenitors that acquire or possess an innate ability to actively remodel the ECM. The apparent capacity of basal cells to adapt their milieu may contribute to basal cell dysfunction in response to severe epithelial injury (57) and chronic lung diseases, including idiopathic pulmonary fibrosis (29).…”

“…Cultures were generated and analyzed according to published methods (5,24,29), and are described in detail in the online supplement.…”

Physiology of the lung in idiopathic pulmonary fibrosis

“…Alveolar lesions conform to the usual interstitial pneumonia (UIP) pattern. The UIP pattern is defined by: 1) spatial heterogeneity, as lesions alternate with areas of normal lung; 2) temporal heterogeneity, with the concomitant presence of discrete lesions in lung tissue that appears otherwise normal (called fibroblastic foci) and fibrotic areas composed mainly of dense acellular collagen; and 3) the presence of honeycomb lesions, which are abnormal dilated airspaces with walls composed of fibrotic tissue, lined by an epithelium that shares characteristics with the airway epithelium [21,22]. Tissular alterations are also present in other parts of the respiratory system in IPF.…”

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

“…While pulmonary inflammation and loss of lung architecture in IPF involve interactions among multiple cell types, recent studies provide increasing support for the concept that injury to the respiratory epithelium plays an important role in IPF pathogenesis (4,5). Loss of normal alveolar architecture in IPF is accompanied by fibrotic remodeling, loss of AT1 and AT2 cells, and the presence of atypical epithelial cells expressing differentiated cell markers characteristic of proximal airways and submucosal glands (e.g., basal cell and goblet cell markers) in the normal lung (6,7). Basal cells in conducting airways, and AT2 cells in the alveoli, serve as progenitor cells, with critical roles in regeneration of the respiratory epithelium following both acute and chronic injury.…”

“…Early in lung morphogenesis, epithelial cell type specification is firmly established, and patterns of gene expression and cell types are not overlapping in conducting versus alveolar regions of the lung. While histopathological analyses of lung tissue from patients with IPF demonstrate abnormalities in the morphology of epithelial cells lining remodeled regions of the peripheral lung parenchyma (6,7), it is presently unclear what mechanisms lead to tissue remodeling and altered epithelial cell fates. Interpretation of proteomic and transcriptomic data obtained from lung tissue in IPF is complicated by the complexity and heterogeneity of tissue changes, obscuring identification of the roles of individual cell types in disease pathogenesis (23).…”