A Hoskins1, P Wu, S Reiss, R Dworski. 1. Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Abstract
BACKGROUND: Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1 Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little remains known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics. OBJECTIVE: To establish the effect of the glutathione S-transferase P1 Ile105Val polymorphism on allergen-induced airway inflammation and oxidant stress, and non-specific bronchial hyperresponsiveness to methacholine and reactivity to specific allergen in mild human atopic asthmatics in vivo. METHODS: Five Val(105)/Val(105) , twelve Val(105)/Ile(105) and twenty Ile(105)/Ile(105) mild atopic asthmatics underwent methacholine challenge, inhaled allergen challenge and endobronchial allergen provocation through a bronchoscope. A panel of inflammatory cytokines and chemokines, F2 -isoprostanes and isofuranes, markers of oxidative stress, thromboxane B2 and immunoglobulin E were measured in bronchoalveolar lavage fluid at baseline and 24 h after allergen instillation. RESULTS: Asthmatics with glutathione S-transferase P1 Val(105)/Val(105) compared with asthmatics with the glutathione S-transferase P1 Val(105)/Ile(105) and Ile(105)/Ile(105) had greater generation of acute phase cytokines (TNF-α, IL-6, CXCL8), IL-12, CCL11, thromboxane B2 and immunoglobulin E at 24 h after local allergen challenge. The GSTP1 genotype had no effect on airway hyperresponsiveness to methacholine and the reactivity to specific allergen. CONCLUSION: The glutathione S-transferase P1 Ile105Val polymorphism markedly modifies allergen-provoked airway inflammation in atopic asthmatics in vivo. Modulation of the biochemical milieu in response to allergen provides a mechanistic explanation for regulatory effects of glutathione S-transferase P1 polymorphism on airway pathophysiology, and may guide improvement of future therapeutic methods in human atopic asthmatics. These findings must me confirmed in a larger study population of asthmatics with various ethnicities.
BACKGROUND:Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little remains known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics. OBJECTIVE: To establish the effect of the glutathione S-transferase P1Ile105Val polymorphism on allergen-induced airway inflammation and oxidant stress, and non-specific bronchial hyperresponsiveness to methacholine and reactivity to specific allergen in mild human atopic asthmatics in vivo. METHODS: Five Val(105)/Val(105) , twelve Val(105)/Ile(105) and twenty Ile(105)/Ile(105) mild atopic asthmatics underwent methacholine challenge, inhaled allergen challenge and endobronchial allergen provocation through a bronchoscope. A panel of inflammatory cytokines and chemokines, F2 -isoprostanes and isofuranes, markers of oxidative stress, thromboxane B2 and immunoglobulin E were measured in bronchoalveolar lavage fluid at baseline and 24 h after allergen instillation. RESULTS: Asthmatics with glutathione S-transferase P1Val(105)/Val(105) compared with asthmatics with the glutathione S-transferase P1Val(105)/Ile(105) and Ile(105)/Ile(105) had greater generation of acute phase cytokines (TNF-α, IL-6, CXCL8), IL-12, CCL11, thromboxane B2 and immunoglobulin E at 24 h after local allergen challenge. The GSTP1 genotype had no effect on airway hyperresponsiveness to methacholine and the reactivity to specific allergen. CONCLUSION: The glutathione S-transferase P1Ile105Val polymorphism markedly modifies allergen-provoked airway inflammation in atopic asthmatics in vivo. Modulation of the biochemical milieu in response to allergen provides a mechanistic explanation for regulatory effects of glutathione S-transferase P1 polymorphism on airway pathophysiology, and may guide improvement of future therapeutic methods in human atopic asthmatics. These findings must me confirmed in a larger study population of asthmatics with various ethnicities.
Authors: D W Cockcroft; B E Davis; L-P Boulet; F Deschesnes; G M Gauvreau; P M O'Byrne; R M Watson Journal: Allergy Date: 2005-01 Impact factor: 13.146
Authors: X Hu; H Xia; S K Srivastava; C Herzog; Y C Awasthi; X Ji; P Zimniak; S V Singh Journal: Biochem Biophys Res Commun Date: 1997-09-18 Impact factor: 3.575
Authors: William W Busse; Adam Wanner; Kenneth Adams; Herbert Y Reynolds; Mario Castro; Badrul Chowdhury; Monica Kraft; Robert J Levine; Stephen P Peters; Eugene J Sullivan Journal: Am J Respir Crit Care Med Date: 2005-07-14 Impact factor: 21.405
Authors: V Adler; Z Yin; S Y Fuchs; M Benezra; L Rosario; K D Tew; M R Pincus; M Sardana; C J Henderson; C R Wolf; R J Davis; Z Ronai Journal: EMBO J Date: 1999-03-01 Impact factor: 11.598
Authors: Amrita Singh; Kashi N Prasad; Aloukick K Singh; Satyendra K Singh; Kamlesh K Gupta; Vimal K Paliwal; Chandra M Pandey; Rakesh K Gupta Journal: Mol Neurobiol Date: 2016-03-28 Impact factor: 5.590
Authors: Francisco J Sánchez-Gómez; Beatriz Díez-Dacal; Elena García-Martín; José A G Agúndez; María A Pajares; Dolores Pérez-Sala Journal: Front Pharmacol Date: 2016-08-04 Impact factor: 5.810