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

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 alpha-tocopherol, alpha-tocopherol transfer protein (alpha TTP). Pulmonary alpha TTP was induced by inspired CO2 in two in vivo murine models of ventilator-induced lung injury; the level of alpha TTP expression correlated with degree of lung protection; and, absence of the alpha TTP gene significantly reduced the protective effects of CO2. alpha-Tocopherol is a potent antioxidant and hypercapnia increased lung alpha-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 alpha TTP-/- mice. In concordance with a regulatory role for alpha-tocopherol in lipid mediator synthesis, hypercapnia attenuated 5-lipoxygenase activity and this was dependent on the presence of alpha TTP. Conclusions Inspired CO2 upregulates alpha TTP which increases lung alpha-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant.