Glutaredoxin deficiency promotes activation of the transforming growth factor beta pathway in airway epithelial cells, in association with fibrotic airway remodeling
Shi B. Chia,
James D. Nolin,
Reem Aboushousha,
Cuixia Erikson,
Charles G. Irvin,
Matthew E. Poynter,
Jos van der Velden,
Douglas J. Taatjes,
Albert van der Vliet,
Vikas Anathy,
Yvonne M.W. Janssen-Heininger
Affiliations
Shi B. Chia
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
James D. Nolin
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, 80206, USA
Reem Aboushousha
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Cuixia Erikson
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Charles G. Irvin
Department of Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Matthew E. Poynter
Department of Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Jos van der Velden
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Douglas J. Taatjes
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Albert van der Vliet
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Vikas Anathy
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
Yvonne M.W. Janssen-Heininger
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA; Corresponding author. Department of Pathology and Laboratory Medicine, University of Vermont Health Sciences Research Facility, Room 216A, Burlington, VT, 05405, USA.
S-glutathionylation of reactive protein cysteines is a post-translational event that plays a critical role in transducing signals from oxidants into biological responses. S-glutathionylation can be reversed by the deglutathionylating enzyme glutaredoxin (GLRX). We have previously demonstrated that ablation of Glrx sensitizes mice to the development of parenchymal lung fibrosis(1). It remains unclear whether GLRX also controls airway fibrosis, a clinical feature relevant to asthma and chronic obstructive pulmonary disease, and whether GLRX controls the biology of airway epithelial cells, which have been implicated in the pathophysiology of these diseases. In the present study we utilized a house dust mite (HDM) model of allergic airway disease in wild type (WT) and Glrx-/- mice on a C57BL/6 background prone to develop airway fibrosis, and tracheal basal stem cells derived from WT mice, global Glrx-/- mice, or bi-transgenic mice allowing conditional ablation of the Glrx gene. Herein we show that absence of Glrx led to enhanced HDM-induced collagen deposition, elevated levels of transforming growth factor beta 1 (TGFB1) in the bronchoalveolar lavage, and resulted in increases in airway hyperresponsiveness. Airway epithelial cells isolated from Glrx-/- mice or following conditional ablation of Glrx showed spontaneous increases in secretion of TGFB1. Glrx-/- basal cells also showed spontaneous TGFB pathway activation, in association with increased expression of mesenchymal genes, including collagen 1a1 and fibronectin. Overall, these findings suggest that GLRX regulates airway fibrosis via a mechanism(s) that involve the plasticity of basal cells, the stem cells of the airways.
