α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury.
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.



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.



Using genome-wide gene expression analysis in a mouse model of ventilator-induced lung injury, we discovered a previously unsuspected mechanism by which CO2can protect against injury: induction of the transporter protein for α-tocopherol, α-tocopherol transfer protein (αTTP). Pulmonary αTTP was induced by inspired CO2in 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.



Inspired CO2upregulates αTTP which increases lung α-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant.
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Gail
G
Otulakowski
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Doreen
D
Engelberts
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hajime
H
Arima
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hiroyuki
H
Hirate
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Hülya
H
Bayir
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Martin
M
Post
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada.|Department of Anesthesia, University of Toronto, Toronto, Canada.
Brian P
BP
Kavanagh
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D055106:Genome-Wide Association Study; D006935:Hypercapnia / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D024502:alpha-Tocopherol / Q000378:metabolism
D002352:Carrier Proteins; D012333:RNA, Messenger; C017763:alpha-tocopherol transfer protein; D007975:Leukotriene B4; D024502:alpha-Tocopherol
ARDS; Assisted Ventilation; Lung Physiology; Respiratory Measurement