Cargando…

Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma

Asthma is characterized by airway inflammation. Inflammation is associated with oxidant stress. Airway epithelial cells are shielded from this stress by a thin layer of lung lining fluid (LLF) which contains an abundance of the antioxidant glutathione. LLF glutathione metabolism is regulated by γ-gl...

Descripción completa

Detalles Bibliográficos
Autores principales: Tuzova, Marina, Jean, Jyh-Chang, Hughey, Rebecca P., Brown, Lou Ann S., Cruikshank, William W., Hiratake, Jun, Joyce-Brady, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116799/
https://www.ncbi.nlm.nih.gov/pubmed/25132819
http://dx.doi.org/10.3389/fphar.2014.00179
_version_ 1782328629497167872
author Tuzova, Marina
Jean, Jyh-Chang
Hughey, Rebecca P.
Brown, Lou Ann S.
Cruikshank, William W.
Hiratake, Jun
Joyce-Brady, Martin
author_facet Tuzova, Marina
Jean, Jyh-Chang
Hughey, Rebecca P.
Brown, Lou Ann S.
Cruikshank, William W.
Hiratake, Jun
Joyce-Brady, Martin
author_sort Tuzova, Marina
collection PubMed
description Asthma is characterized by airway inflammation. Inflammation is associated with oxidant stress. Airway epithelial cells are shielded from this stress by a thin layer of lung lining fluid (LLF) which contains an abundance of the antioxidant glutathione. LLF glutathione metabolism is regulated by γ-glutamyl transferase (GGT). Loss of LLF GGT activity in the mutant GGT(enu1) mouse causes an increase in baseline LLF glutathione content which is magnified in an IL-13 model of allergic airway inflammation and protective against asthma. Normal mice are susceptible to asthma in this model but can be protected with acivicin, a GGT inhibitor. GGT is a target to treat asthma but acivicin toxicity limits clinical use. GGsTop is a novel GGT inhibitor. GGsTop inhibits LLF GGT activity only when delivered through the airway. In the IL-13 model, mice treated with IL-13 and GGsTop exhibit a lung inflammatory response similar to that of mice treated with IL-13 alone. But mice treated with IL-13 and GGsTop show attenuation of methacholine-stimulated airway hyper-reactivity, inhibition of Muc5ac and Muc5b gene induction, decreased airway epithelial cell mucous accumulation and a fourfold increase in LLF glutathione content compared to mice treated with IL-13 alone. Mice treated with GGsTop alone are no different from that of mice treated with saline alone, and show no signs of toxicity. GGsTop could represent a valuable pharmacological tool to inhibit LLF GGT activity in pulmonary disease models. The associated increase in LLF glutathione can protect lung airway epithelial cells against oxidant injury associated with inflammation in asthma.
format Online
Article
Text
id pubmed-4116799
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-41167992014-08-15 Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma Tuzova, Marina Jean, Jyh-Chang Hughey, Rebecca P. Brown, Lou Ann S. Cruikshank, William W. Hiratake, Jun Joyce-Brady, Martin Front Pharmacol Pharmacology Asthma is characterized by airway inflammation. Inflammation is associated with oxidant stress. Airway epithelial cells are shielded from this stress by a thin layer of lung lining fluid (LLF) which contains an abundance of the antioxidant glutathione. LLF glutathione metabolism is regulated by γ-glutamyl transferase (GGT). Loss of LLF GGT activity in the mutant GGT(enu1) mouse causes an increase in baseline LLF glutathione content which is magnified in an IL-13 model of allergic airway inflammation and protective against asthma. Normal mice are susceptible to asthma in this model but can be protected with acivicin, a GGT inhibitor. GGT is a target to treat asthma but acivicin toxicity limits clinical use. GGsTop is a novel GGT inhibitor. GGsTop inhibits LLF GGT activity only when delivered through the airway. In the IL-13 model, mice treated with IL-13 and GGsTop exhibit a lung inflammatory response similar to that of mice treated with IL-13 alone. But mice treated with IL-13 and GGsTop show attenuation of methacholine-stimulated airway hyper-reactivity, inhibition of Muc5ac and Muc5b gene induction, decreased airway epithelial cell mucous accumulation and a fourfold increase in LLF glutathione content compared to mice treated with IL-13 alone. Mice treated with GGsTop alone are no different from that of mice treated with saline alone, and show no signs of toxicity. GGsTop could represent a valuable pharmacological tool to inhibit LLF GGT activity in pulmonary disease models. The associated increase in LLF glutathione can protect lung airway epithelial cells against oxidant injury associated with inflammation in asthma. Frontiers Media S.A. 2014-07-31 /pmc/articles/PMC4116799/ /pubmed/25132819 http://dx.doi.org/10.3389/fphar.2014.00179 Text en Copyright © 2014 Tuzova, Jean, Hughey, Brown, Cruikshank, Hiratake and Joyce-Brady. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Tuzova, Marina
Jean, Jyh-Chang
Hughey, Rebecca P.
Brown, Lou Ann S.
Cruikshank, William W.
Hiratake, Jun
Joyce-Brady, Martin
Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title_full Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title_fullStr Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title_full_unstemmed Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title_short Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma
title_sort inhibiting lung lining fluid glutathione metabolism with ggstop as a novel treatment for asthma
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116799/
https://www.ncbi.nlm.nih.gov/pubmed/25132819
http://dx.doi.org/10.3389/fphar.2014.00179
work_keys_str_mv AT tuzovamarina inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT jeanjyhchang inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT hugheyrebeccap inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT brownlouanns inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT cruikshankwilliamw inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT hiratakejun inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma
AT joycebradymartin inhibitinglungliningfluidglutathionemetabolismwithggstopasanoveltreatmentforasthma