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Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-beta 1-dependent mechanism

Lookup NU author(s): Marta Gorowiec, Dr Lee Borthwick, Dr Sean Parker, Emeritus Professor John Kirby, Dr Gabriele Saretzki, Professor Andrew FisherORCiD

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Abstract

Fibrotic remodelling of lung parenchymal and airway compartments is the major contributor to life-threatening organ dysfunction in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD). Since transforming growth factor-beta (TGF-beta 1) is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage (BAL) from such patients we sought to investigate whether both factors might be interrelated. Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition (EMT) via the augmentation of TGF-beta 1. We show that in response to 400 mu M hydrogen peroxide (H2O2) A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells (PBECs) undergo EMT displaying morphology changes, decreased expression of epithelial markers (E-cadherin and ZO-1), increased expression of mesenchymal markers (vimentin and alpha-smooth muscle actin) as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of TGF-beta 1. Inhibition of TGF-beta 1 signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone (PBN) and superoxide dismutase 3 (SOD3) prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes. This study identifies a link between oxidative stress, TGF-beta 1 and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease. (C) 2012 Elsevier Inc. All rights reserved.

Publication metadata

Author(s): Gorowiec MR, Borthwick LA, Parker SM, Kirby JA, Saretzki GC, Fisher AJ

Publication type: Article

Publication status: Published

Journal: Free Radical Biology & Medicine

Year: 2012

Volume: 52

Issue: 6

Pages: 1024-1032

Print publication date: 02/01/2012

ISSN (print): 0891-5849

ISSN (electronic): 1873-4596

Publisher: Elsevier Inc.

URL: http://dx.doi.org/10.1016/j.freeradbiomed.2011.12.020

DOI: 10.1016/j.freeradbiomed.2011.12.020

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