High Concentration Hydrogen Mitigates Sepsis-Induced Acute Lung Injury in Mice by Alleviating Mitochondrial Fission and Dysfunction

Abstract

Background: Multiple organ failure (MOF) is the main cause of early death in septic shock. Lungs are among the organs that are affected in MOF, resulting in acute lung injury. A large number of inflammatory factors and stress injury in sepsis can lead to alterations in mitochondrial dynamics. Numerous studies have confirmed that hydrogen can alleviate sepsis in the animal model. The purpose of this experiment was to explore the therapeutic effect of high concentration (67%) hydrogen on acute lung injury in septic mice and its mechanism. Methods: The moderate and severe septic models were prepared by cecal ligation and puncture. Hydrogen with different concentrations was inhaled for one hour at 1 h and 6 h after the corresponding surgery. The arterial blood gas of mice during hydrogen inhalation was monitored in real time, and the 7-day survival rate of mice with sepsis was recorded. The pathological changes of lung tissues and functions of livers and kidneys were measured. The changes of oxidation products, antioxidant enzymes and pro-inflammatory cytokines in lungs and serums were detected. Mitochondrial function was measured. Results: The inhalation of 2% or 67% hydrogen improves the 7-day survival rate and reduces acute lung injury as well as liver and kidney injury in sepsis. The therapeutic effect of 67% hydrogen inhalation on sepsis was related to increasing antioxidant enzyme activity, reducing oxidation products and pro-inflammatory cytokines in lungs and serums. Compared with the Sham group, mitochondrial dysfunction was alleviated in hydrogen groups. Conclusions: Hydrogen inhalation by high or low concentration can both significantly improve sepsis; however, a high concentration demonstrates a better protective effect. High concentration hydrogen inhalation can significantly improve the mitochondrial dynamic balance and reduce the lung injury in septic mice.

Mitochondria: one of the vital hubs for molecular hydrogen’s biological functions

“…Notably, in such tumor cells, H 2 demonstrates a significant ability to activate the mtUPR response, likely attributed to the high basal and spare mitochondrial electron transport chain (ETC) activities of these types of tumor cells (Hasegawa et al, 2022). In addition, in terms of certain mitochondrial indicators, such as complex II activity and the expression of complex II, III and V, remain largely unchanged after hydrogen treatment in both the LPS-induced ALI (Fan et al, 2022) and septic mouse models (Dong et al, 2018;Xie et al, 2021;Zhao et al, 2023), which may be attributed to the fact that external stress did not significantly affect these indicators in the model group. In conclusion, H 2 has a significant mitigating effect on altered mitochondrial function caused by external stress.…”

“…The net balance between fission and fusion dynamically regulates the number and morphology of mitochondria (Chan, 2020). Previous studies have provided both in vivo and in vitro evidence that H 2 could alleviate lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-induced mitochondrial fission and promote mitochondrial fusion, evidenced by downregulation of Drp1 expression and upregulation of MFN1/2 or OPA1 expression (Dong et al, 2018;Lian et al, 2022;Zhang et al, 2023;Zhao et al, 2023). Lian et al showed that H 2 had a similar inhibitory effect to Mdivi-1, a mitochondrial fission blocker, on LPS-induced upregulation of Drp1 and its recruitment to mitochondria, which further confirmed the suppressing role of H 2 on LPS-induced mitochondrial fission (Lian et al, 2022).…”

Protective Effect of Vitamin K2 (MK-7) on Acute Lung Injury Induced by Lipopolysaccharide in Mice

“…There is overwhelming evidence that mitochondrial dysfunction plays a vital role in the etiology of ALI [ 10 , 11 ]. Mitochondria are the site of oxidative metabolism in eukaryotes, which serve as scaffolds to initiate protein–protein signaling, and regulate Ca 2+ homeostasis and reactive oxygen species (ROS) [ 12 ]. Mitochondria are also involved in autophagy, mitophagy, cell death signaling, and innate immune responses [ 13 ].…”