Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze.

Thomas Iosifidis,Anthony Kicic,Darryl A Knight,Luke W Garratt,Jessica Hillas,Kak-Ming Ling,Shyan Vijayasekaran,Paul J Rigby,Erika N Sutanto,Nicole C Shaw,Kelly M Martinovich,Francis J Lannigan,Samuel T Montgomery,Patricia Agudelo-Romero,Stephen M Stick,Kevin Looi,Elizabeth Kicic-Starcevich

doi:10.3390/jpm11121323

Abstract

The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.

Highlights

IntroductionIn children, wheezing illnesses and asthma exacerbations are some of the most common causes of hospital presentation with current treatments targeting symptoms (e.g., bronchoconstriction and airway inflammation) and not the underlying mechanisms
In children, wheezing illnesses and asthma exacerbations are some of the most common causes of hospital presentation with current treatments targeting symptoms and not the underlying mechanisms
To address whether Notch signaling is dysregulated in airway epithelial samples from children with wheeze, we initially performed a meta-analysis of relevant pediatric-specific published transcriptomic datasets [30,31] to identify any association of Notch signaling with recurrent wheeze, and/or epithelial injury and repair

Summary

Introduction

In children, wheezing illnesses and asthma exacerbations are some of the most common causes of hospital presentation with current treatments targeting symptoms (e.g., bronchoconstriction and airway inflammation) and not the underlying mechanisms. Despite these treatments, young children experience recurrent and severe wheezing that may develop in chronic asthma in later childhood and adulthood. Understanding the underlying disease mechanisms that dysregulate airway epithelial repair in early childhood could identify new areas for targeted therapies to halt wheeze recurrence and prevent asthma development

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Results

Conclusion