Pulmonary Veno-Occlusive Disease(PVOD)is a rare but severe condition.It is marked by narrowing of the pulmonary veins,which gradually increases pulmonary arterial pressure and vascular resistance,making it a subtype of Pulmonary Arterial Hypertension(PAH).
PVOD develops silently,is difficult to diagnose,and is often identified late,leading to poor outcomes[1,2].Current treatment options are limited,and effective therapies are still lacking.
To address this,a research team led by Wang Jian at Guangzhou Medical University conducted experiments on hydrogen inhalation.Their findings,published in Respiratory Research under the title“Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease”,suggest promising protective effects of hydrogen therapy[3].
Hydrogen-Oxygen Therapy and Pulmonary Veno-Occlusive DiseaseRecent studies have shown that certain chemotherapy drugs may increase the risk of developing PVOD[4].
Given hydrogen-oxygen’s beneficial effects on multiple organ systems—its ability to reduce inflammation and oxidative stress—hydrogen-oxygen inhalation could offer a novel approach not only for preventing and treating pulmonary hypertension but also for alleviating chemotherapy-related side effects.
This study explored the preventive and therapeutic effects of hydrogen inhalation in a rat model of mitomycin C(MMC)-induced PVOD.
Potential Mechanism Model of Hydrogen Alleviating PVOD
Experimental Methods
Female rats were used to establish the PVOD model through intraperitoneal injections of MMC(3 mg·kg⁻¹per week)for two consecutive weeks.Hydrogen-oxygen inhalation was delivered using the Asclepius hydrogen-oxygen generator.
Grouping and Procedures of Different Experimental Protocols
The study was divided into four groups:Normal Control(N,n=15),MMC Treatment(MMC,n=15),Hydrogen-Oxygen Prevention(HP,n=15),and Hydrogen-Oxygen Treatment(HT,n=15).Rats in the control group received an equivalent volume of 0.9%saline instead of MMC.In the HP group,hydrogen-oxygen inhalation was administered simultaneously with MMC injections,serving as a preventive intervention before disease onset.In the HT group,hydrogen-oxygen inhalation started two weeks after the initial MMC injection,representing a therapeutic intervention.
Experimental Results
1.In both the preventive and treatment groups,hydrogen-oxygen inhalation effectively mitigated MMC-induced weight loss and high mortality.As shown in the figure below:
Body weight changes and survival rate
II.Hydrogen-Oxygen Inhalation Reduces Pulmonary Inflammation and Oxidative Stress in MMC-Induced PVOD Rats
Exposure to MMC caused a marked increase in inflammatory cytokines,including IL-1β,IL-6,IL-8,IL-17,and TNF-α,indicating systemic inflammation(Figures a–e).MMC-treated rats also showed elevated malondialdehyde(MDA)levels,a marker of lipid peroxidation(Figure f).However,hydrogen-oxygen inhalation significantly prevented and reversed these increases in inflammatory markers and MDA,demonstrating that H₂inhalation can effectively inhibit oxidative stress and reduce lung inflammation caused by MMC exposure.
Hydrogen-Oxygen Inhalation Improves Lung Inflammation and Oxidative Stress Indicators
III.Hydrogen-Oxygen Inhalation Reverses MMC-Induced Pulmonary Vascular Remodeling in PVOD Rats.
Compared with the control group,MMC exposure caused significant thickening of the medial layer of pulmonary vascular smooth muscle.In addition,there was notable overlap betweenα-SMA and vWF,indicating endothelial-to-mesenchymal transition(EndoMT).These changes are hallmark features of PVOD-related pulmonary vascular remodeling.Hydrogen-oxygen inhalation substantially restored normal vascular structure,effectively reversing MMC-induced vascular remodeling.
Immunofluorescence double staining was performed usingα-SMA(a smooth muscle cell marker,labeled green)and vWF(von Willebrand factor,an endothelial cell marker,labeled red).
IV.Hydrogen-oxygen inhalation exerts therapeutic effects by acting as an inhibitory EndoMT mediator through Smads signaling.
The study found that hydrogen-oxygen inhalation significantly reversed the expression of EndoMT-related proteins in both preventive and therapeutic settings.Specifically,inhalation inhibited MMC-induced upregulation of p-Smad1/5/9 and GCN2 while restoring the MMC-induced reduction of p-Smad3.
Summary
These results provide strong evidence that hydrogen-oxygen inhalation offers significant preventive and therapeutic benefits for MMC-induced PVOD in a rat model.The therapeutic effects appear to involve modulation of key inflammatory and oxidative stress pathways,including GCN2 and HO-1.
With its antioxidant properties and minimal side effects,hydrogen-oxygen inhalation shows great promise as an effective,safe,and potentially transformative approach for the treatment of pulmonary arterial hypertension,meriting further investigation.
References[1]Montani D,Lau EM,Dorfmüller P,Girerd B,Jaïs X,Savale L,Perros F,Nossent E,Garcia G,Parent F,et al.Pulmonary veno-occlusive disease.Eur Respir J.2016;47:1518–34.[2]Simonneau G,Montani D,Celermajer DS,Denton CP,Gatzoulis MA,Krowka M,Williams PG,Souza R.Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J 2019,53.[3]Zhang C,Xing Y,Wu X,Jiang Q,Luo X,He W,Liu S,Lu W,Wang J.Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease.Respir Res.2024 Jul 16;25(1):281.[4]Ranchoux B,Günther S,Quarck R,Chaumais MC,Dorfmüller P,Antigny F,Dumas SJ,Raymond N,Lau E,Savale L,et al.Chemotherapy-induced pulmonary hypertension:role of alkylating agents.Am J Pathol.2015;185:356–71. 
