title: Activating transcription factor 3 confers protection against ventilator-induced lung injury.
abstract: 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.
authors.affiliation: Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Akram
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Hussain
authors.initials: H
authors.lastname: Masoom
authors.forename: Claudia
authors.initials: C
authors.lastname: Peng
authors.forename: Emily
authors.initials: E
authors.lastname: Lam
authors.forename: Michael L
authors.initials: ML
authors.lastname: Litvack
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Bai
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Shan
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.forename: Jane
authors.initials: J
authors.lastname: Batt
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Haitsma
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Claudia C
authors.initials: CC
authors.lastname: dos Santos
mesh_terms: 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*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497108:Atf3 protein, rat; D016207:Cytokines