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.

Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis

“…The gain-of-function variant of MUC5B promoter is an acknowledged risk factor for the development of IPF (Seibold et al, 2011), and one animal study also evidenced that selective overexpression of MUC5B in bronchoalveolar epithelial cells augmented bleomycininduced lung fibrosis (Hancock, et al, 2018). Recently, Stancil et al (2021) have demonstrated that one copy (GT) of MUC5B promoter variant prolonged the persistence of amphiregulin-induced unjammed phase in IPF-derived airway epithelial cells as compared to the no copy (GG) variant, while epithelial cells with this unjammed phase promoted proliferation and activation of human lung fibroblasts. As for the ciliary abnormality, it is unclear whether it happened before or after the disease onset.…”

“…All histologic sections from the control subjects and patients with IPF were digitally scanned by using a digital pathological section scanner (PRECICE500B, Beijing, China). According to a recent paper published by (Okuda et al, 2019), the airways were classified as 1) bronchi [defined as airways with cartilage support and submucosal glands (SMGs)]; 2) proximal bronchioles (defined as airways with no cartilage support or SMGs, surrounded by smooth muscle bands and characterized by an undulating epithelium, with 1-2 mm in diameter); 3) distal bronchioles in control subjects (defined as a structure with a lesswrinkled epithelium compared with the proximal bronchioles, with <1 mm in diameter; and 4) distal bronchioles in IPF patients (defined as a structure with a less-wrinkled epithelium and surrounded by fibrosis in honeycomb cysts, with <1 mm in diameter) (Ikezoe et al, 2021;Stancil et al, 2021).…”

EGFR Signaling in Lung Fibrosis

“…YAP is a transcriptional co-activator, which was found to regulate epithelial progenitor cell proliferation in the lung [104] and epithelialmesenchymal transition in lung cancer cells following exposure to TGF-β [105]. These findings are supported by the increased levels of AREG in IPF distal airway epithelial cells and its ability to induce jammed to unjammed transition in controlling distal airway epithelial cells in vitro [103]. Interestingly, the AREG-triggered extended unjammed phase of distal airway epithelial cells correlated with activation of the fibroblasts lying underneath [103], thus providing ample evidence for the contribution of airways epithelial cells repopulating distal parts of IPF lungs to the disease progression.…”

“…It was also associated with the pathogenesis of carcinomas [101] and asthma [102]. Stancil et al [103] demonstrated in vitro that the unjammed phase is extended in distal airway epithelial cells of IPF patients and is associated with increased activity of the ErbB-YAP (Yes-Associated Protein) signaling pathway. YAP is a transcriptional co-activator, which was found to regulate epithelial progenitor cell proliferation in the lung [104] and epithelialmesenchymal transition in lung cancer cells following exposure to TGF-β [105].…”

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

“…Although pulmonary fibrosis pathobiology has been focused on interactions within the alveolus, there is a growing understanding of the role of the distal airway epithelium 55 , 75 , 76 . The distal airway is known to be essential to alveolar repair after severe injury and it is hypothesized that dysregulation of this repair pathway may be related to distal airspace remodeling, including bronchiolization and honeycombing, seen in pulmonary fibrosis 55 , 77 .…”