title: Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease.
abstract: Protein-S-glutathionylation (PSSG) is an oxidative modification of reactive cysteines that has emerged as an important player in pathophysiological processes. Under physiological conditions, the thiol transferase, glutaredoxin-1 (Glrx1) catalyses deglutathionylation. Although we previously demonstrated that Glrx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/PSSG in the development of allergic airways disease remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness (AHR) in mice. Glrx1(-/-) or WT mice were subjected to the antigen, ovalbumin (OVA), and parameters of allergic airways disease were evaluated 48 h after three challenges, and 48 h or 7 days after six challenges with aerosolized antigen. Although no clear increases in PSSG were observed in WT mice in response to OVA, marked increases were detected in lung tissue of mice lacking Glrx1 48 h following six antigen challenges. Inflammation and expression of proinflammatory mediators were decreased in Glrx1(-/-) mice, dependent on the time of analysis. WT and Glrx1(-/-) mice demonstrated comparable increases in AHR 48 h after three or six challenges with OVA. However, 7 days postcessation of six challenges, parameters of AHR in Glrx1(-/-) mice were resolved to control levels, accompanied by marked decreases in mucus metaplasia and expression of Muc5AC and GOB5. These results demonstrate that the Glrx1/S-glutathionylation redox status in mice is a critical regulator of AHR, suggesting that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.
authors: Departments of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA.
authors: Sidra M
authors: SM
authors: Hoffman
authors: Jane E
authors: JE
authors: Tully
authors: Karolyn G
authors: KG
authors: Lahue
authors: Vikas
authors: V
authors: Anathy
authors: James D
authors: JD
authors: Nolin
authors: Amy S
authors: AS
authors: Guala
authors: Jos L J
authors: JL
authors: van der Velden
authors: Ye-Shih
authors: YS
authors: Ho
authors: Minara
authors: M
authors: Aliyeva
authors: Nirav
authors: N
authors: Daphtary
authors: Lennart K A
authors: LK
authors: Lundblad
authors: Charles G
authors: CG
authors: Irvin
authors: Yvonne M W
authors: YM
authors: Janssen-Heininger
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D054477:Glutaredoxins / Q000172:deficiency / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000473:pathology; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D009093:Mucus; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000209:etiology; D011506:Proteins / Q000378:metabolism
chemical_list: D054477:Glutaredoxins; D011506:Proteins; D010047:Ovalbumin; D005978:Glutathione