title: Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Kathy T
authors.initials: KT
authors.lastname: Schroer
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gibson
authors.forename: Umasundari
authors.initials: U
authors.lastname: Sivaprasad
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Bass
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: Tim
authors.initials: T
authors.lastname: Lecras
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fitzpatrick
authors.forename: Lou Ann S
authors.initials: LA
authors.lastname: Brown
authors.forename: Keith F
authors.initials: KF
authors.lastname: Stringer
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
mesh_terms: D000293:Adolescent; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction; D012882:Skin Tests
chemical_list: D000485:Allergens; D051549:Glutathione S-Transferase pi