Effect of Transcriptional Regulatory Factor FoxO3a on Central Nervous System Oxygen Toxicity

Yanan Zhang,Ping Hu,Chengwei Xie,Yuliang Chen,Runping Li,Guoyang Huang,Benming You,Junlin Yang

doi:10.3389/fphys.2020.596326

Abstract

Central nervous system (CNS) oxygen toxicity (CNS-OT) is a toxic reaction that appears after the inhalation of gas at an excessive oxygen partial pressure during underwater operation or hyperbaric oxygen (HBO) treatment. The mechanism of CNS-OT has not been clearly characterized. Though it has been attributed to the excessive oxidative stress induced by HBO, evidences against this hypothesis have been reported. Here we find that Forkhead box protein O3 (FoxO3a) is important for CNS-OT protection. FoxO3a knock-out (KO) mice had a shorter latency to develop convulsions and greater number of seizures within a certain period of time. The acute lung injury (ALI) induced by CNS-OT was also more severe in FoxO3a KO mice. Further analysis reveals a significant decrease in the activity of catalase (CAT), an antioxidant enzyme and a significant increase in the content of malondialdehyde (MDA), an oxidative product, in brain tissues of FoxO3a KO mice. Short-time HBO exposure could increase FoxO3a expression level and trigger its nuclear translocation. The level of nuclear localized FoxO3a peaked at 8 h after exposure. Our results demonstrate that the activity of FoxO3a is highly sensitive to HBO exposure and FoxO3a plays important roles in protecting CNS-OT. Further mechanic analysis reveals that FoxO3a protects CNS-OT via activating antioxidative signaling pathway.

Highlights

Hyperbaric oxygen (HBO) is widely applied in underwater missions, hyperbaric facility operation and disease treatment
Histopathological examination of the lungs showed that, compared with wild type FVB mice (WT mice) without hyperbaric oxygen (HBO) exposure, both HBOexposed WT mice and FoxO3a KO mice developed lung injury characterized by hemorrhage, and FoxO3a KO mice had more severe congestion in the bronchiolar wall and alveolar tissues, more inflammatory cell infiltration, and more disorganized lung tissue structures (Figure 2)
It is mainly considered that HBO exposure can lead to the increase of oxygen content in tissues, far exceeding the capacity of mitochondria to completely reduce it to H2O molecules through cellular respiration

Summary

Introduction

Hyperbaric oxygen (HBO) is widely applied in underwater missions, hyperbaric facility operation and disease treatment. After inhalation of the gas with high oxygen partial pressure (OPP) for time beyond a limit, a toxic reaction, i.e., oxygen toxicity (OT), occurs. When the OPP is greater than 3 ATA, OT is characterized by central nervous system (CNS) dysfunction as the main manifestation, called CNS-OT, and the most typical and intense manifestation is grand mal seizure, that is, “oxygen convulsion” (Zhu et al, 2016; Wingelaar et al, 2017; Ciarlone et al, 2019). The exact pathogenesis of oxygen convulsion remains to be explored. Effect of FoxO3a on CNS-OT available preventive measures are to restrict OPP and shorten the oxygen inhalation duration. The protective effects of these measures are limited

Methods

Results

Conclusion