Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

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• 作者：Kathy T.  ; Schroer PhD^a ; Aaron M.  ; Gibson BS^a ; Umasundari  ; Sivaprasad PhD^a ; Stacey A.  ; Bass^a ; Mark B.  ; Ericksen BS^a ; Marsha  ; Wills-Karp PhD^a ; Tim  ; LeCras PhD^a ; Anne M.  ; Fitzpatrick PhD^b ; Lou Ann S.  ; Brown PhD^b ; Keith F.  ; Stringer MD^a ; Gurjit K. Khurana  ; Hershey MD ; PhD^a ;   ; ^{Gurjit.Khurana.Hershey@cchmc.org}
• 关键词：Glutathione S-transferase pi ; asthma ; oxidative stress ; redox homeostasis ; gene
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：September 2011
• 年：2011
• 卷：128
• 期：3
• 页码：539-548
• 全文大小：1073 K

文摘

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¨Ctreated murine models of asthma through signal transducer and activator of transcription 6¨Cdependent and independent pathways. Nuclear factor erythroid 2¨Crelated 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.