The relation between age and airway epithelial barrier function

M de Vries; K O Nwozor; K Muizer; M Wisman; W Timens; M van den Berge; A Faiz; T-L Hackett; I H Heijink; C A Brandsma

doi:10.1186/s12931-022-01961-7

The relation between age and airway epithelial barrier function

Respir Res. 2022 Mar 3;23(1):43. doi: 10.1186/s12931-022-01961-7.

Authors

M de Vries^#^{1

2}, K O Nwozor^#^{3

4

5}, K Muizer^{3

4}, M Wisman^{3

4}, W Timens^{3

4}, M van den Berge^{3

6}, A Faiz^{3

4

6}, T-L Hackett⁵, I H Heijink^#^{3

4

6}, C A Brandsma^#^{3

4}

Affiliations

¹ University Medical Center Groningen, University of Groningen, Department of Epidemiology, Hanzeplein 1, 9713, Groningen, The Netherlands. m.de.vries04@umcg.nl.
² University Medical Center Groningen, University of Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands. m.de.vries04@umcg.nl.
³ University Medical Center Groningen, University of Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
⁴ University Medical Center Groningen, University of Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.
⁵ Department of Anesthesiology, Pharmacology & Therapeutics, Centre for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada.
⁶ University Medical Center Groningen, University of Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.

^# Contributed equally.

Abstract

Background: The prevalence of age-associated diseases, such as chronic obstructive pulmonary disease (COPD), is increasing as the average life expectancy increases around the world. We previously identified a gene signature for ageing in the human lung which included genes involved in apical and tight junction assembly, suggesting a role for airway epithelial barrier dysfunction with ageing.

Aim: To investigate the association between genes involved in epithelial barrier function and age both in silico and in vitro in the airway epithelium.

Methods: We curated a gene signature of 274 genes for epithelial barrier function and tested the association with age in two independent cohorts of bronchial brushings from healthy individuals with no respiratory disease, using linear regression analysis (FDR < 0.05). Protein-protein interactions were identified using STRING©. The barrier function of primary bronchial epithelial cells at air-liquid interface and CRISPR-Cas9-induced knock-down of target genes in human bronchial 16HBE14o-cells was assessed using Trans epithelial resistance (TER) measurement and Electric cell-surface impedance sensing (ECIS) respectively.

Results: In bronchial brushings, we found 55 genes involved in barrier function to be significantly associated with age (FDR < 0.05). EPCAM was most significantly associated with increasing age and TRPV4 with decreasing age. Protein interaction analysis identified CDH1, that was negatively associated with higher age, as potential key regulator of age-related epithelial barrier function changes. In vitro, barrier function was lower in bronchial epithelial cells from subjects > 45 years of age and significantly reduced in CDH1-deficient 16HBE14o-cells.

Conclusion: The significant association between genes involved in epithelial barrier function and age, supported by functional studies in vitro, suggest a role for epithelial barrier dysfunction in age-related airway disease.

Keywords: Ageing; Airway epithelial cells; CDH1; Chronic airway diseases; EPCAM; Epithelial barrier function.

MeSH terms

Adolescent
Adult
Aged
Aging / physiology*
Bronchi / metabolism*
Bronchi / pathology
Cells, Cultured
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Female
Humans
Male
Middle Aged
Pulmonary Disease, Chronic Obstructive / metabolism*
Pulmonary Disease, Chronic Obstructive / pathology
Respiratory Mucosa / metabolism
Young Adult