scholarly journals Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 430
Author(s):  
Catharina van Heusden ◽  
Barbara R. Grubb ◽  
Brian Button ◽  
Eduardo R. Lazarowski
Keyword(s):  
Epithelial Cells ◽  
Mucociliary Clearance ◽  
Atp Release ◽  
Airway Epithelial Cells ◽  
Lubricant Layer ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Pannexin 1 ◽  
Dominant Component ◽  
Chronic Obstructive Lung Diseases

Mucociliary clearance (MCC) is a dominant component of pulmonary host defense. In health, the periciliary layer (PCL) is optimally hydrated, thus acting as an efficient lubricant layer over which the mucus layer moves by ciliary force. Airway surface dehydration and production of hyperconcentrated mucus is a common feature of chronic obstructive lung diseases such as cystic fibrosis (CF) and chronic bronchitis (CB). Mucus hydration is driven by electrolyte transport activities, which in turn are regulated by airway epithelial purinergic receptors. The activity of these receptors is controlled by the extracellular concentrations of ATP and its metabolite adenosine. Vesicular and conducted pathways contribute to ATP release from airway epithelial cells. In this study, we review the evidence leading to the identification of major components of these pathways: (a) the vesicular nucleotide transporter VNUT (the product of the SLC17A9 gene), the ATP transporter mediating ATP storage in (and release from) mucin granules and secretory vesicles; and (b) the ATP conduit pannexin 1 expressed in non-mucous airway epithelial cells. We further illustrate that ablation of pannexin 1 reduces, at least in part, airway surface liquid (ASL) volume production, ciliary beating, and MCC rates.

scholarly journals CiliOPD: a ciliopathy-associated COPD endotype

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jeanne-Marie Perotin ◽  
Myriam Polette ◽  
Gaëtan Deslée ◽  
Valérian Dormoy
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Epithelial Cells ◽  
Mucociliary Clearance ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Remodelling ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Small Airway Epithelial Cells

AbstractThe pathophysiology of chronic obstructive pulmonary disease (COPD) relies on airway remodelling and inflammation. Alterations of mucociliary clearance are a major hallmark of COPD caused by structural and functional cilia abnormalities. Using transcriptomic databases of whole lung tissues and isolated small airway epithelial cells (SAEC), we comparatively analysed cilia-associated and ciliopathy-associated gene signatures from a set of 495 genes in 7 datasets including 538 non-COPD and 508 COPD patients. This bio-informatics approach unveils yet undescribed cilia and ciliopathy genes associated with COPD including NEK6 and PROM2 that may contribute to the pathology, and suggests a COPD endotype exhibiting ciliopathy features (CiliOPD).

scholarly journals Overproduction of growth differentiation factor 15 promotes human rhinovirus infection and virus-induced inflammation in the lung

2018 ◽  
Vol 314 (3) ◽  
pp. L514-L527 ◽  
Author(s):  
Qun Wu ◽  
Di Jiang ◽  
Niccolette R. Schaefer ◽  
Laura Harmacek ◽  
Brian P. O’Connor ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Responses ◽  
Airway Epithelial Cells ◽  
Human Rhinovirus ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Growth Differentiation Factor 15 ◽  
Human Airway ◽  
Differentiation Factor ◽  
Human Airway Epithelial Cells

Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. Therefore, in the current study, we investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation. We first examined the role of GDF15 in regulating host defense and HRV-induced inflammation using human GDF15 transgenic mice and cultured human GDF15 transgenic mouse tracheal epithelial cells. Next, we determined the effect of GDF15 on viral replication, antiviral responses, and inflammation in human airway epithelial cells with GDF15 knockdown and HRV infection. Finally, we explored the signaling pathways involved in airway epithelial responses to HRV infection in the context of GDF15. Human GDF15 protein overexpression in mice led to exaggerated inflammatory responses to HRV, increased infectious particle release, and decreased IFN-λ2/3 (IL-28A/B) mRNA expression in the lung. Moreover, GDF15 facilitated HRV replication and inflammation via inhibiting IFN-λ1/IL-29 protein production in human airway epithelial cells. Lastly, Smad1 cooperated with interferon regulatory factor 7 (IRF7) to regulate airway epithelial responses to HRV infection partly via GDF15 signaling. Our results reveal a novel function of GDF15 in promoting lung HRV infection and virus-induced inflammation, which may be a new mechanism for the increased susceptibility and severity of respiratory viral (i.e., HRV) infection in cigarette smoke-exposed airways with GDF15 overproduction.

scholarly journals Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function

2021 ◽  
Vol 134 (4) ◽  
pp. jcs257162 ◽  
Author(s):  
Corrine R. Kliment ◽  
Jennifer M. K. Nguyen ◽  
Mary Jane Kaltreider ◽  
YaWen Lu ◽  
Steven M. Claypool ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Adenine Nucleotide ◽  
Airway Epithelial Cells ◽  
Adenine Nucleotide Translocase ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Ciliary Function ◽  
Transporter Family ◽  
Surface Hydration

ABSTRACTAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.This article has an associated First Person interview with the first author of the paper.

scholarly journals ACE2 Expression is elevated in Airway Epithelial Cells from aged and male donors but reduced in asthma

2020 ◽  
Author(s):  
Peter Wark ◽  
Prabuddha Pathinyake ◽  
Gerard Kaiko ◽  
Kristy Nichol ◽  
Ayesha Ali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Serine Proteases ◽  
Airway Epithelial Cells ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Asthma Patients

Rationale: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter airway epithelial cells (AECs). Objective: To determine what factors are associated with ACE2 expression particularly in patients with asthma and chronic obstructive pulmonary disease (COPD). Methods: We obtained upper and lower AECs from 145 people from two independent cohorts, aged 2-89, Newcastle (n=115), and from Perth (n= 30) Australia. The Newcastle cohort was enriched with people with asthma (n=37) and COPD (n=38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry were assessed by quantitative PCR, protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AECs. Results: Increased gene expression of ACE2 was associated with older age (p=0.02) and male sex (p=0.03), but not pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma (p=0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in asthma (p=0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface was increased (p=0.02). ACE2 protein levels were lower in endobronchial biopsies from asthma patients. Conclusions: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.

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