Activating transcription factor 3 confers protection against ventilator-induced lung injury.
BACKGROUND
Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority.


OBJECTIVE
To identify specific molecular regulators involved in the development of VILI.


METHODS
We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene-deficient mice to wild-type mice in an in vivo model of VILI.


RESULTS
ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cis-regulatory regions was significantly altered in ATF3-deficient mice.


CONCLUSIONS
ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume-induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.
Akram
Ali
A
Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
Han
Bing
B
Masoom
Hussain
H
Peng
Claudia
C
Lam
Emily
E
Litvack
Michael L
ML
Bai
Xiaohui
X
Shan
Yuexin
Y
Hai
Tsonwin
T
Batt
Jane
J
Slutsky
Arthur S
AS
Zhang
Haibo
H
Kuebler
Wolfgang M
WM
Haitsma
Jack J
JJ
Liu
Mingyao
M
dos Santos
Claudia C
CC
D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000517:prevention & control*
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497108:Atf3 protein, rat; D016207:Cytokines