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 Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function

2020 ◽  
Author(s):  
Corrine R. Kliment ◽  
Jennifer M. K. Nguyen ◽  
Mary Jane Kaltreider ◽  
YaWen Lu ◽  
Steven M. Claypool ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Adenine Nucleotide ◽  
Genetic Selection ◽  
Chronic Obstructive Lung Disease ◽  
Airway Epithelial Cells ◽  
Mitochondrial Metabolism ◽  
Adenine Nucleotide Translocase ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Ciliary Function

AbstractAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4th leading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoeba Dictyostelium discoideum as a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT’s presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.

Cigarette smoke irreversibly modifies glutathione in airway epithelial cells

2007 ◽  
Vol 293 (5) ◽  
pp. L1156-L1162 ◽  
Author(s):  
Marco van der Toorn ◽  
Maria P. Smit-de Vries ◽  
Dirk-Jan Slebos ◽  
Harold G. de Bruin ◽  
Nicolas Abello ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
A549 Cells ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Gsh Metabolism ◽  
Primary Bronchial Epithelial Cells

In patients with chronic obstructive pulmonary disease (COPD), an imbalance between oxidants and antioxidants is acknowledged to result in disease development and progression. Cigarette smoke (CS) is known to deplete total glutathione (GSH + GSSG) in the airways. We hypothesized that components in the gaseous phase of CS may irreversibly react with GSH to form GSH derivatives that cannot be reduced (GSX), thereby causing this depletion. To understand this phenomenon, we investigated the effect of CS on GSH metabolism and identified the actual GSX compounds. CS and H2O2 (control) deplete reduced GSH in solution [Δ = −54.1 ± 1.7 μM ( P < 0.01) and −39.8 ± 0.9 μM ( P < 0.01), respectively]. However, a significant decrease of GSH + GSSG was observed after CS (Δ = −75.1 ± 7.6 μM, P < 0.01), but not after H2O2. Exposure of A549 cells and primary bronchial epithelial cells to CS decreased free sulfhydryl (-SH) groups (Δ = −64.2 ± 14.6 μM/mg protein, P < 0.05) and irreversibly modified GSH + GSSG (Δ = −17.7 ± 1.9 μM, P < 0.01) compared with nonexposed cells or H2O2 control. Mass spectrometry (MS) showed that GSH was modified to glutathione-aldehyde derivatives. Further MS identification showed that GSH was bound to acrolein and crotonaldehyde and another, yet to be identified, structure. Our data show that CS does not oxidize GSH to GSSG but, rather, reacts to nonreducible glutathione-aldehyde derivatives, thereby depleting the total available GSH pool.

scholarly journals Antibacterial Defense of Human Airway Epithelial Cells from Chronic Obstructive Pulmonary Disease Patients Induced by Acute Exposure to Nontypeable Haemophilus influenzae: Modulation by Cigarette Smoke

2017 ◽  
Vol 9 (4) ◽  
pp. 359-374 ◽  
Author(s):  
Gimano D. Amatngalim ◽  
Jasmijn A. Schrumpf ◽  
Almira Henic ◽  
Esther Dronkers ◽  
Renate M. Verhoosel ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Antibacterial Activity ◽  
Epithelial Cells ◽  
Haemophilus Influenzae ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Nontypeable Haemophilus Influenzae ◽  
Obstructive Pulmonary Disease

Antimicrobial proteins and peptides (AMPs) are a central component of the antibacterial activity of airway epithelial cells. It has been proposed that a decrease in antibacterial lung defense contributes to an increased susceptibility to microbial infection in smokers and patients with chronic obstructive pulmonary disease (COPD). However, whether reduced AMP expression in the epithelium contributes to this lower defense is largely unknown. We investigated the bacterial killing activity and expression of AMPs by air-liquid interface-cultured primary bronchial epithelial cells from COPD patients and non-COPD (ex-)smokers that were stimulated with nontypeable Haemophilus influenzae (NTHi). In addition, the effect of cigarette smoke on AMP expression and the activation of signaling pathways was determined. COPD cell cultures displayed reduced antibacterial activity, whereas smoke exposure suppressed the NTHi-induced expression of AMPs and further increased IL-8 expression in COPD and non-COPD cultures. Moreover, smoke exposure impaired NTHi-induced activation of NF-κB, but not MAP-kinase signaling. Our findings demonstrate that the antibacterial activity of cultured airway epithelial cells induced by acute bacterial exposure was reduced in COPD and suppressed by cigarette smoke, whereas inflammatory responses persisted. These findings help to explain the imbalance between protective antibacterial and destructive inflammatory innate immune responses in COPD.

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 4‐Methylumbelliferone Prevents E‐cadherin Downregulation Induced by Cigarette Smoke in Airway Epithelial Cells

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Maria Elena Monzon Medina ◽  
Monica Valencia ◽  
Rosanna Malbran Forteza ◽  
Marina Casalino-Matsuda
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
E Cadherin
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