ATP7B detoxifies silver in ciliated airway epithelial cells

Ibricevic, Aida

doi:10.1016/j.taap.2009.11.023

Title: ATP7B detoxifies silver in ciliated airway epithelial cells

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Abstract

Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increasedmore »« less

Authors:

Ibricevic, Aida ^[1]

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States)

Publication Date:: Mon Mar 15 00:00:00 EDT 2010

OSTI Identifier:: 21344889

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 243; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2009.11.023; PII: S0041-008X(09)00496-7; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ACETATES; ANTIBIOTICS; APOPTOSIS; CAFFEINE; COPPER; COPPER IONS; DETOXIFICATION; IN VITRO; LUNGS; MICE; SENSITIVITY; SILVER; SILVER IONS; ANALEPTICS; ANIMALS; ANTI-INFECTIVE AGENTS; AROMATICS; AZAARENES; BODY; CARBOXYLIC ACID SALTS; CENTRAL NERVOUS SYSTEM AGENTS; CHARGED PARTICLES; DRUGS; ELEMENTS; HETEROCYCLIC COMPOUNDS; IONS; MAMMALS; METALS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; ORGANS; PURINES; RESPIRATORY SYSTEM; RODENTS; TRANSITION ELEMENTS; VERTEBRATES; XANTHINES

Citation Formats


                    Ibricevic, Aida, Brody, Steven L., E-mail: sbrody@dom.wustl.ed, Youngs, Wiley J., E-mail: youngs@uakron.ed, and Cannon, Carolyn L., E-mail: carolyn.cannon@utsouthwestern.ed. ATP7B detoxifies silver in ciliated airway epithelial cells.  United States: N. p., 2010. 
        Web.  doi:10.1016/j.taap.2009.11.023.

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                    Ibricevic, Aida, Brody, Steven L., E-mail: sbrody@dom.wustl.ed, Youngs, Wiley J., E-mail: youngs@uakron.ed, & Cannon, Carolyn L., E-mail: carolyn.cannon@utsouthwestern.ed. ATP7B detoxifies silver in ciliated airway epithelial cells.  United States.  https://doi.org/10.1016/j.taap.2009.11.023

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                    Ibricevic, Aida, Brody, Steven L., E-mail: sbrody@dom.wustl.ed, Youngs, Wiley J., E-mail: youngs@uakron.ed, and Cannon, Carolyn L., E-mail: carolyn.cannon@utsouthwestern.ed. 2010.  
        "ATP7B detoxifies silver in ciliated airway epithelial cells".  United States.  https://doi.org/10.1016/j.taap.2009.11.023.

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@article{osti_21344889,

  title        = {ATP7B detoxifies silver in ciliated airway epithelial cells},

  author       = {Ibricevic, Aida and Brody, Steven L., E-mail: sbrody@dom.wustl.ed and Youngs, Wiley J., E-mail: youngs@uakron.ed and Cannon, Carolyn L., E-mail: carolyn.cannon@utsouthwestern.ed},

  abstractNote = {Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA-treated HepG2 cells. In addition, mTEC from ATP7B{sup -/-} mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell type-specific expression of the Ag{sup +}/Cu{sup +} transporters ATP7A, ATP7B, and CTR1 in airway epithelial cells and a role for ATP7B in detoxification of these metals in the lung.},

  doi          = {10.1016/j.taap.2009.11.023},

  url          = {https://www.osti.gov/biblio/21344889},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 243,

  place        = {United States},

  year         = {Mon Mar 15 00:00:00 EDT 2010},

  month        = {Mon Mar 15 00:00:00 EDT 2010}

}

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