Asthma and lower airway disease
Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

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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.

Section snippets

Subjects

Recruitment, nasal mucosal sampling, and RNA isolation from children with and without asthma were previously described.22 Briefly, after institutional review board approval was obtained, healthy and asthmatic children (age 5-18 years old) presenting to Cincinnati Children’s Hospital Medical Center were invited to participate in the study. Asthma was diagnosed in accordance with American Thoracic Society criteria.7, 8 All the children had positive skin prick test responses to at least 1

GSTPi expression and total GST activity are decreased in allergen-challenged mice

We examined GSTPi expression and total GST activity in several different murine models of asthma. Challenge with HDM or A fumigatus induced a significant increase in AHR, as measured by means of APTI after allergen challenge, as previously expected (data not shown). Contrary to expectations, we observed a marked decrease in the level of GSTPi mRNA expression in the lungs of mice after HDM or A fumigatus challenge compared with that seen in control mice (Fig 1, A and C). We also observed a

Discussion

The contribution of GSTPi to asthma has been supported by epidemiologic, genetic, and animal studies by our group and others,14, 15, 16, 17, 21 although the mechanism for this has remained elusive. Our findings provide important novel insights into the contribution of GSTPi to asthma in human subjects and mice. Given that several environmental exposures associated with asthma result in enhanced oxidative stress, one might predict that GST enzymes would be induced to increase the capacity to

References (52)

  • P. Sharma et al.

    Redox regulation of interleukin-4 signaling

    Immunity

    (2008)
  • B. Bloom et al.

    Summary health statistics for U.S. children: National Health Interview Survey, 2004

    Vital Health Stat 10

    (2006)
  • C. Ober et al.

    Asthma genetics 2006: the long and winding road to gene discovery

    Genes Immun

    (2006)
  • D. Diaz-Sanchez et al.

    Diesel effects on human health: a question of stress?

    Am J Physiol Lung Cell Mol Physiol

    (2005)
  • D.J. Conklin et al.

    Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke

    Am J Physiol Heart Circ Physiol

    (2009)
  • D.B. Peden

    Development of atopy and asthma: candidate environmental influences and important periods of exposure

    Environ Health Perspect

    (2000)
  • M. Waegemaekers et al.

    Respiratory symptoms in damp homes. A pilot study

    Allergy

    (1989)
  • J.D. Hayes et al.

    The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance

    Crit Rev Biochem Mol Biol

    (1995)
  • B. Mannervik et al.

    Nomenclature for human glutathione transferases

    Biochem J

    (1992)
  • T. Kano et al.

    Structure and expression of a human class pi glutathione S-transferase messenger RNA

    Cancer Res

    (1987)
  • I.J. Doull et al.

    Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness

    Am J Respir Crit Care Med

    (1996)
  • L. Tamer et al.

    Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma

    Respirology

    (2004)
  • F.D. Gilliland et al.

    Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth

    Am J Respir Crit Care Med

    (2002)
  • A.A. Fryer et al.

    Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma

    Am J Respir Crit Care Med

    (2000)
  • K.T. Schroer et al.

    Associations between multiple environmental exposures and glutathione S-transferase P1 on persistent wheezing in a birth cohort

    J Pediatr

    (2009)
  • S. Michel et al.

    Unifying candidate gene and GWAS approaches in asthma

    PLoS One

    (2010)
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    Supported by National Institutes of Health grant U19A170235 (G.K.K.H.).

    Disclosure of potential conflict of interest: T. LeCras receives research support from the National Institutes of Health (NIH) and the American Heart Association. A. M. Fitzpatrick receives research support from the NIH; the National Heart, Lung, and Blood Institute; and the National Institute of Nursing Research. G. K. K. Hershey receives research support from the NIH. The rest of the authors have declared that they have no conflict of interest.

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