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Published Online: 17 November 2014

ATF3 Protects Pulmonary Resident Cells from Acute and Ventilator-Induced Lung Injury by Preventing Nrf2 Degradation

Publication: Antioxidants & Redox Signaling
Volume 22, Issue Number 8

Abstract

Aims: Ventilator-induced lung injury (VILI) contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). Absence of activating transcription factor 3 (ATF3) confers susceptibility to ALI/VILI. To identify cell-specific ATF3-dependent mechanisms of susceptibility to ALI/VILI, we generated ATF3 chimera by adoptive bone marrow (BM) transfer and randomized to inhaled saline or lipopolysacharide (LPS) in the presence of mechanical ventilation (MV). Adenovirus vectors to silence or overexpress ATF3 were used in primary human bronchial epithelial cells and murine BM-derived macrophages from wild-type or ATF3-deficient mice. Results: Absence of ATF3 in myeloid-derived cells caused increased pulmonary cellular infiltration. In contrast, absence of ATF3 in parenchymal cells resulted in loss of alveolar-capillary membrane integrity and increased exudative edema. ATF3-deficient macrophages were unable to limit the expression of pro-inflammatory mediators. Knockdown of ATF3 in resident cells resulted in decreased junctional protein expression and increased paracellular leak. ATF3 overexpression abrogated LPS induced membrane permeability. Despite release of ATF3-dependent Nrf2 transcriptional inhibition, mice that lacked ATF3 expression in resident cells had increased Nrf2 protein degradation. Innovation: In our model, in the absence of ATF3 in parenchymal cells increased Nrf2 degradation is the result of increased Keap-1 expression and loss of DJ-1 (Parkinson disease [autosomal recessive, early onset] 7), previously not known to play a role in lung injury. Conclusion: Results suggest that ATF3 confers protection to lung injury by preventing inflammatory cell recruitment and barrier disruption in a cell-specific manner, opening novel opportunities for cell specific therapy for ALI/VILI. Antioxid. Redox Signal. 22, 651–668.

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cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 22Issue Number 8March 10, 2015
Pages: 651 - 668
PubMed: 25401197

History

Published in print: March 10, 2015
Published ahead of print: 19 January 2015
Published online: 17 November 2014
Accepted: 20 October 2014
Revision received: 25 September 2014
Received: 9 May 2014

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Yuexin Shan
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Ali Akram*
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Hajera Amatullah
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
Dun Yuan Zhou
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada.
Patricia L. Gali
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Tatiana Maron-Gutierrez
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Adrian González-López
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
Louis Zhou
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Patricia R.M. Rocco
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
David Hwang
Department of Clinical Pathology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada.
Guillermo M. Albaiceta
Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
Jack J. Haitsma
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Department of Anesthesiology and Intensive Care, Lund University Hospital, Lund, Sweden.
Claudia C. dos Santos
Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada.

Notes

*
Current affiliation: Toronto Western Hospital (UHN), University of Toronto, Toronto, Canada.
Address correspondence to:Dr. Claudia C. dos SantosInterdepartmental Division of Critical CareSt. Michael's HospitalUniversity of Toronto30 Bond Street, Room 4-008Toronto, ON, M5B 1WBCanada
E-mail: [email protected]

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