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...
Autores principales: | , , , , , , |
---|---|
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 |