Interactions between the Bronchial Epithelium and Fibrocytes in the Pathogenesis of Airway Remodeling in Asthma

Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based onin silicoanalysis and followed byin vitrovalidation. In summary, thein silicoanalysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.

Download Full-text

Characterizing smoking-induced transcriptional heterogeneity in the human bronchial epithelium at single-cell resolution

10.1101/484394 ◽

2018 ◽

Author(s):

Grant E. Duclos ◽

Vitor H. Teixeira ◽

Patrick Autissier ◽

Yaron B. Gesthalter ◽

Marjan A. Reinders-Luinge ◽

...

Keyword(s):

Single Cell ◽

Airway Remodeling ◽

Bronchial Epithelium ◽

Cell Types ◽

Premalignant Lesions ◽

Specific Cell ◽

Cell Hyperplasia ◽

Bronchial Epithelial ◽

Molecular Alterations ◽

Distinct Cell

ABSTRACTThe human bronchial epithelium is composed of multiple, distinct cell types that cooperate to perform functions, such as mucociliary clearance, that defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, the precise effects of this exposure on specific cell types are not well-understood. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never- and six current smokers. Unsupervised analyses identified thirteen cell clusters defined by unique combinations of nineteen distinct gene sets. Expression of a set of toxin metabolism genes localized to ciliated cells from smokers. Smoking-induced airway remodeling was characterized by a loss of club cells and extensive goblet cell hyperplasia. Finally, we identified a novel peri-goblet epithelial subpopulation in smokers that expressed a marker of bronchial premalignant lesions. Our data demonstrates that smoke exposure drives a complex landscape of cellular and molecular alterations in the human bronchial epithelium that may contribute to the onset of smoking-associated lung diseases.

Download Full-text

GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610433113 ◽

2016 ◽

Vol 113 (46) ◽

pp. 13132-13137 ◽

Cited By ~ 48

Author(s):

Sudipta Das ◽

Marina Miller ◽

Andrew K. Beppu ◽

James Mueller ◽

Matthew D. McGeough ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Inflammation ◽

Airway Hyperresponsiveness ◽

Genetic Linkage ◽

Airway Remodeling ◽

Bronchial Epithelium ◽

Asthma Phenotype ◽

Expression Of Genes ◽

Tgf Β1

Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-β1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMBZp3-Cre mice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMBZp3-Cre mice showed increases in the same remodeling and AHR mediators (TGF-β1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-β1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells overexpressing GSDMB inhibited TGF-β1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-β1 in bronchial epithelium.

Download Full-text