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α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury
  1. Gail Otulakowski1,
  2. Doreen Engelberts1,
  3. Hajime Arima1,2,3,
  4. Hiroyuki Hirate1,2,3,
  5. Hülya Bayir4,5,
  6. Martin Post1,
  7. Brian P Kavanagh1,2,6
  1. 1Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada
  2. 2Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada
  3. 3Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  4. 4Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  5. 5Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  6. 6Department of Anesthesia, University of Toronto, Toronto, Canada
  1. Correspondence to Dr Brian P Kavanagh, Department of Critical Care Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; brian.kavanagh{at}


Rationale Hypercapnia is common in mechanically ventilated patients. Experimentally, ‘therapeutic hypercapnia’ can protect, but it can also cause harm, depending on the mechanism of injury. Hypercapnia suppresses multiple signalling pathways. Previous investigations have examined mechanisms that were known a priori, but only a limited number of pathways, each suppressed by CO2, have been reported.

Objective Because of the complexity and interdependence of processes in acute lung injury, this study sought to fill in knowledge gaps using an unbiased screen, aiming to identify a specifically upregulated pathway.

Methods and results Using genome-wide gene expression analysis in a mouse model of ventilator-induced lung injury, we discovered a previously unsuspected mechanism by which CO2 can protect against injury: induction of the transporter protein for α-tocopherol, α-tocopherol transfer protein (αTTP). Pulmonary αTTP was induced by inspired CO2 in two in vivo murine models of ventilator-induced lung injury; the level of αTTP expression correlated with degree of lung protection; and, absence of the αTTP gene significantly reduced the protective effects of CO2. α-Tocopherol is a potent antioxidant and hypercapnia increased lung α-tocopherol in wild-type mice, but this did not alter superoxide generation or expression of NRF2-dependent antioxidant response genes in wild-type or in αTTP−/− mice. In concordance with a regulatory role for α-tocopherol in lipid mediator synthesis, hypercapnia attenuated 5-lipoxygenase activity and this was dependent on the presence of αTTP.

Conclusions Inspired CO2 upregulates αTTP which increases lung α-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant.

  • ARDS
  • Assisted Ventilation
  • Lung Physiology
  • Respiratory Measurement

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  • Contributors GO conceived the study, conducted the study, and analysed the data. DE, HA and HH participated in study design, conducted experiments, analysed data. HB, MP and BPK participated in study design, data analysis and interpretation. All authors participated in drafting or critically revising the manuscript and approved the final version.

  • Funding Institute of Circulatory and Respiratory Health (FRN 69006).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Primary microarray datasets are accessible through NCBI GEO (series accession number GSE86229).

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