Alpha-1 antitrypsin mitigates the inhibition of airway epithelial cell repair by neutrophil elastase

Copyright © 2016 by the American Thoracic Society. Neutrophil elastase (NE) activity is associated with many destructive lung diseases and is a predictor for structural lung damage in early cystic fibrosis (CF), which suggests normal maintenance of airway epitheliumis prevented byuninhibitedNE.However, limited data exist on how the NE activity in airways of very young children with CF affects function of the epithelia. The aimof this studywas to determine if NE activity could inhibit epithelial homeostasis and repair and whether any functional effect was reversible by antiprotease alpha-1 antitrypsin (a1AT) treatment. Viability, inflammation, apoptosis, and proliferation were assessed in healthy non-CF and CF pediatric primary airway epithelial cells (pAEC non-CF and pAEC CF , respectively) during exposure to physiologically relevant NE. The effect of NE activity on pAEC CF wound repair was also assessed.We report that viability after 48 hours was significantly decreased by 100 nM NE in pAEC non-CF and pAEC CF owing to rapid cellular detachment that was accompanied by inflammatory cytokine release. Furthermore, both phenotypes initiated an apoptotic response to 100 nM NE, whereas ≥50 nM NE activity significantly inhibited the proliferative capacity of cultures. Similar concentrations of NE also significantly inhibited wound repair of pAEC CF , but this effect was reversed by the addition of a1AT. Collectively, our results demonstrate free NE activity is deleterious for epithelial homeostasis and support the hypothesis that proteases inthe airway contribute directly toCF structural lung disease. Our results also highlight the need to investigate antiprotease therapies in early CF disease in more detail

Absent otoacoustic emissions predict otitis media in young Aboriginal children: A birth cohort study in Aboriginal and non-Aboriginal children in an arid zone of Western Australia

Background: Otitis media (OM) is the most common paediatric illness for which antibiotics are prescribed. In Australian Aboriginal children OM is frequently asymptomatic and starts at a younger age, is more common and more likely to result in hearing loss than in non-Aboriginal children. Absent transient evoked otoacoustic emissions (TEOAEs) may predict subsequent risk of OM. Methods: 100 Aboriginal and 180 non-Aboriginal children in a semi-arid zone of Western Australia were followed regularly from birth to age 2 years. Tympanometry was conducted at routine field follow-up from age 3 months. Routine clinical examination by an ENT specialist was to be done 3 times and hearing assessment by an audiologist twice. TEOAEs were measured at ages <1 and 1-2 months. Cox proportional hazards model was used to investigate the association between absent TEOAEs and subsequent risk of OM. Results: At routine ENT specialist clinics, OM was detected in 55% of 184 examinations in Aboriginal children and 26% of 392 examinations in non-Aboriginal children; peak prevalence was 72% at age 5-9 months in Aboriginal children and 40% at 10-14 months in non-Aboriginal children. Moderate-severe hearing loss was present in 32% of 47 Aboriginal children and 7% of 120 non-Aboriginal children aged 12 months or more. TEOAE responses were present in 90% (46/51) of Aboriginal children and 99% (120/121) of non-Aboriginal children aged <1 month and in 62% (21/ 34) and 93% (108/116), respectively, in Aboriginal and non-Aboriginal children at age 1-2 months. Aboriginal children who failed TEOAE at age 1-2 months were 2.6 times more likely to develop OM subsequently than those who passed. Overall prevalence of type B tympanograms at field follow-up was 50% (n = 78) in Aboriginal children and 20% (n = 95) in non-Aboriginal children. Conclusion: The burden of middle ear disease is high in all children, but particularly in Aboriginal children, one-third of whom suffer from moderate-severe hearing loss. In view of the frequently silent nature of OM, every opportunity must be taken to screen for OM. Measurement of TEOAEs at age 1-2 months to identify children at risk of developing OM should be evaluated in a routine health service setting

Assessing the unified airway hypothesis in children via transcriptional profiling of the airway epithelium

© 2020 American Academy of Allergy, Asthma & Immunology Background: Emerging evidence suggests that disease vulnerability is expressed throughout the airways, the so-called unified airway hypothesis, but the evidence to support this is predominantly indirect. Objectives: We sought to establish the transcriptomic profiles of the upper and lower airways and determine their level of similarity irrespective of airway symptoms (wheeze) and allergy. Methods: We performed RNA sequencing on upper and lower airway epithelial cells from 63 children with or without wheeze and accompanying atopy, using differential gene expression and gene coexpression analyses to determine transcriptional similarity. Results: We observed approximately 91% homology in the expressed genes between the 2 sites. When coexpressed genes were grouped into modules relating to biological functions, all were found to be conserved between the 2 regions, resulting in a consensus network containing 16 modules associated with ribosomal function, metabolism, gene expression, mitochondrial activity, and antiviral responses through IFN activity. Although symptom-associated gene expression changes were more prominent in the lower airway, they were reflected in nasal epithelium and included IL-1 receptor like 1, prostaglandin-endoperoxide synthase 1, CCL26, and periostin. Through network analysis we identified a cluster of coexpressed genes associated with atopic wheeze in the lower airway, which could equally distinguish atopic and nonatopic phenotypes in upper airway samples. Conclusions: We show that the upper and lower airways are significantly conserved in their transcriptional composition, and that variations associated with disease are present in both nasal and tracheal epithelium. Findings from this study supporting a unified airway imply that clinical insight regarding the lower airway in health and disease can be gained from studying the nasal epithelium