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ABSTRACT: Background
Glutathione S-transferase pi (GSTPi) is the predominant redox regulator in the lung. Although evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive.Objectives
We sought to determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis.Methods
We elucidated the regulation of GSTPi in children with asthma and used murine models of asthma to determine the role of GSTPi in redox homeostasis.Results
Our findings demonstrate that GSTPi transcript levels are markedly downregulated in allergen- and IL-13-treated murine models of asthma through signal transducer and activator of transcription 6-dependent and independent pathways. Nuclear factor erythroid 2-related factor 2 was also downregulated in these models. The decrease in GSTPi expression was associated with decreased total glutathione S-transferase activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating cysteine oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in percentage cystine) compared with wild-type mice after allergen challenge. GSTPi expression was similarly downregulated in children with asthma.Conclusions
These data collectively suggest that downregulation of GSTPi after allergen challenge might contribute to the asthma phenotype because of disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi might be an important therapeutic target for asthma, and evaluation of GSTPi expression might prove beneficial in identifying patients who would benefit from therapy targeting this pathway.
SUBMITTER: Schroer KT
PROVIDER: S-EPMC3164907 | biostudies-literature | 2011 Sep
REPOSITORIES: biostudies-literature
Schroer Kathy T KT Gibson Aaron M AM Sivaprasad Umasundari U Bass Stacey A SA Ericksen Mark B MB Wills-Karp Marsha M Lecras Tim T Fitzpatrick Anne M AM Brown Lou Ann S LA Stringer Keith F KF Hershey Gurjit K Khurana GK
The Journal of allergy and clinical immunology 20110513 3
<h4>Background</h4>Glutathione S-transferase pi (GSTPi) is the predominant redox regulator in the lung. Although evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive.<h4>Objectives</h4>We sought to determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis.<h4>Methods</h4>We elucidated the regulation of GSTPi in children with asthma and used murine models of asthma to determine the role of GSTPi in redox ...[more]