ATF3 protects pulmonary resident cells from acute and ventilator-induced lung injury by preventing Nrf2 degradation.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
1 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 .
Yuexin
Y
Shan
Ali
A
Akram
Hajera
H
Amatullah
Dun Yuan
DY
Zhou
Patricia L
PL
Gali
Tatiana
T
Maron-Gutierrez
Adrian
A
González-López
Louis
L
Zhou
Patricia R M
PR
Rocco
David
D
Hwang
Guillermo M
GM
Albaiceta
Jack J
JJ
Haitsma
Claudia C
CC
dos Santos
D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D002678:Chimera; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism*
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse