The Degradation of Airway Epithelial Tight Junctions in Asthma Under High Airway Pressure Is Probably Mediated by Piezo-1.

Jia Zhou,Xiang-Dong Zhou,Victor P Kolosov,Rui Xu,Bin Li,Juliy M Perelman,Xian-Zhi Du,Guo-Yue Zhang,Ling-Xiu Chen,Qi Li

doi:10.3389/fphys.2021.637790

Abstract

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+]i) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+]i/calpain signaling in the regulation of small airway TJs under extra pressure stimulation.

Highlights

Asthma, one of the most common chronic respiratory inflammatory disease worldwide, is characterized by airway hyperresponsiveness and variable airflow obstruction, followed by airway epithelial repair and remodeling (Dhami et al, 2015)
Full functioning of the airway physical barrier depends on cellular integrity with the expression and coordinate interaction of a series of proteins formed in cell-cell junctional complexes called tight junctions (TJs) (Godfrey, 1997)
Piezo-1 Might Be Responsible for the Alterations in the Increased Airway Permeability in Asthmatic Model Mice

Summary

Introduction

One of the most common chronic respiratory inflammatory disease worldwide, is characterized by airway hyperresponsiveness and variable airflow obstruction, followed by airway epithelial repair and remodeling (Dhami et al, 2015). Due to its physical barrier function, the respiratory epithelium acts as the first protective defence against allergens, viruses, microorganisms. Full functioning of the airway physical barrier depends on cellular integrity with the expression and coordinate interaction of a series of proteins formed in cell-cell junctional complexes called tight junctions (TJs) (Godfrey, 1997). The degradation of TJ proteins and subsequent increase in airway epithelial cell permeability are involved in the process of airway hyperreactivity and exacerbation of asthma. These findings have been demonstrated by the collection of bronchial biopsy samples from asthma patients (Xiao et al, 2011)

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