ATP12A promotes mucus dysfunction during Type 2 airway inflammation

Lennox, Alison; Coburn, Stefanie L.; Leech, John A.; Heidrich, Elisa; Kleyman, Thomas R.; Wenzel, Sally E.; Pilewski, Joseph M.; Corcoran, Timothy E.; Myerburg, Mike M.

doi:10.1038/s41598-018-20444-8

Cited by 37 publications

(52 citation statements)

References 59 publications

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“…Cultures were layered overnight with FITC-dextran (70 kDa; Sigma-Aldrich). After treatments, emission from FITC-labeled mucus layer was recorded as previously described (28,29). Photobleaching was done at Page 9 of 64 10% of full laser power for 2 iterations (~500 ms).…”

Section: Fluorescence Recovery After Photobleaching (Frap)mentioning

confidence: 99%

Electronic Cigarette Vapor with Nicotine Causes Airway Mucociliary Dysfunction Preferentially via TRPA1 Receptors

Chung

Baumlin

Dennis

et al. 2019

Am J Respir Crit Care Med

100

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of Health (NIH) -F32-HL140729 (to S.C.) and R01 HL139365 (to M.S.) RUNNING TITLE: Vaped nicotine impairs mucociliary function preferentially via TRPA1 SUBJECT CATEGORY DESCRIPTOR: 6.17 Smoking Health Effects TOTAL WORD COUNT: 3985 AT A GLANCE COMMENTARY: Scientific Knowledge on the Subject E-cigarettes are marketed as safer alternatives to conventional cigarettes due to their defined composition and noncombustible nature. However, it is unclear how exposure to e-cigarette vapor, colloquially referred to as "vape", affects naïve airway epithelia. It is largely unknown to what extent individual constituents of vape, such as nicotine and flavoring agents, influence pulmonary function, if at all. The transient receptor potential ankyrin 1 (TRPA1) is a molecular target for vape effects due to its expression in airway epithelia and its reported gating by nicotine, reactive oxidants, and flavors, especially cinnamaldehyde. What This Study Adds to the FieldThis study implicates nicotine as a key "vape" constituent that acutely impairs airway mucociliary functions in vitro and in vivo (sheep). A functional, nicotine-sensitive TRPA1 receptor is natively expressed in human and sheep bronchial epithelial cells and mediates the effects of nicotine and e-cigarette vapors. Importantly, its inhibition prevents mucociliary dysfunction in vitro and in vivo. These findings implicate TRPA1 as a driver of mucociliary dysfunction induced by nicotine-containing e-cigarette vapor.ABSTRACT RATIONALE: Electronic cigarette (e-cig) use has been widely adopted under the perception of safety. However, possibly adverse effects of e-cig vapor in never-smokers are not well understood. OBJECTIVES:Effects of nicotine-containing e-cig vapors on airway mucociliary function were tested in differentiated human bronchial epithelial cells (HBECs) isolated from never-smokers and in the airways of a novel, ovine large animal model. METHODS:Mucociliary parameters were measured in HBECs and in sheep. Systemic nicotine delivery to sheep was quantified using plasma cotinine levels, measured by ELISA. MEASUREMENTS AND MAIN RESULTS:In vitro, exposure to e-cig vapor reduced airway surface liquid hydration and increased mucus viscosity of HBECs in a nicotinedependent manner. Acute nicotine exposure increased intracellular calcium levels, an effect primarily dependent on transient receptor potential ankyrin 1 (TRPA1). TRPA1 inhibition with A967079 restored nicotine-mediated impairment of mucociliary parameters including mucus transport in vitro. Sheep tracheal mucus velocity (TMV), an in vivo measure of mucociliary clearance, was also reduced by e-cig vapor. Nebulized e-cig liquid containing nicotine also reduced TMV in a dose-dependent manner and elevated plasma cotinine levels. Importantly, nebulized A967079 reversed the effects of e-cig liquid on sheep TMV. CONCLUSIONS:Our findings show that inhalation of e-cig vapor causes airway mucociliary dysfunction in vitro and in vivo. Furthermore, they suggest that the main Page 4 of 64 2 nicotine effect on mucociliary ...

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Section: Fluorescence Recovery After Photobleaching (Frap)mentioning

confidence: 99%

Electronic Cigarette Vapor with Nicotine Causes Airway Mucociliary Dysfunction Preferentially via TRPA1 Receptors

Chung

Baumlin

Dennis

et al. 2019

Am J Respir Crit Care Med

100

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“…ATP12A -the nongastric form of the H + /K + -ATPase (10), which is localized on the apical membrane of airway epithelial cells (3,5,11) -is one of the ion transporters involved in ASL pH regulation. ATP12A is emerging as an important pathogenic factor in CF and other chronic respiratory diseases such as asthma (3,12,13). Indeed, in normal airways, the proton secretion operated by ATP12A is expected to be compensated by the parallel bicarbonate transport.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of ATP12A proton pump in cystic fibrosis airways

Scudieri¹,

Musante²,

Caci³

et al. 2018

JCI Insight

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“…NHBEs were used from a total of five different normal human subjects. Cells attained from the University of Pittsburgh cell core were attained as previously described [40,41] with a protocol approved by the University of Pittsburgh Investigational Review Board. NHBEs were grown to 80-90% confluence in collagen-coated flasks then seeded onto Type I collagen-coated (50 µg/mL in 0.02N acetic acid) transparent PET transwell inserts (0.4-µm pore, 24-well insert size 0.33 cm 2 and 12-well insert size 1.12 cm 2 , Corning Costar) at a density of ~5-6 x 10 5 cells/cm 2 .…”

Section: Sources Of Primary Normal Human Bronchial Epithelial Cells (mentioning

confidence: 99%

“…Studies using human tissues were approved by the University of Pittsburgh and Johns HopkinsInstitutional Review Boards (IRB) in accordance with ethical guidelines. For immunohistochemical studies, donor human lung tissue (control and COPD patients) was attained and approved through the National Heart, Lung, and Blood Institute's Lung Tissue Research Consortium database and the Center for Organ Recovery and Education (CORE) at the University of Pittsburgh[40,41]. Human lung tissues used for real time PCR were obtained from explanted lungs after lung transplantation or donor lungs not suitable for organ transplantation (The Airway Cell and Tissue Core, supported by P30 DK072506, NIDDK and the CFF RDP to the University of Pittsburgh).…”

mentioning

confidence: 99%

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

Kliment

Nguyen

Kaltreider

et al. 2020

Preprint

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The authors have declared no conflicts of interest exist. AbstractAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4 th 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. ANT1and 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.

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ATP12A promotes mucus dysfunction during Type 2 airway inflammation

Cited by 37 publications

References 59 publications

Electronic Cigarette Vapor with Nicotine Causes Airway Mucociliary Dysfunction Preferentially via TRPA1 Receptors

Electronic Cigarette Vapor with Nicotine Causes Airway Mucociliary Dysfunction Preferentially via TRPA1 Receptors

Increased expression of ATP12A proton pump in cystic fibrosis airways

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

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