Key Takeaways & Executive Findings
- •• • Hydrogen inhalation at 2% concentration significantly improved cerebral ischemia reperfusion injury in rats (Ohsawa et al., 2007), establishing a baseline for therapeutic dosing in preclinical models. • • Hydrogen-rich saline protects against oxygen glucose deprivation and reperfusion-induced apoptosis via VDAC1 and Bcl-2 pathways (Mo et al., 2019), indicating a molecular mechanism for cytoprotection. • • Hydrogen gas attenuates hypoxic-ischemic brain injury via regulation of the MAPK/HO-1/PGC-1a pathway in neonatal rats (Wang et al., 2020), demonstrating multi-pathway modulation. • • Hydrogen-rich saline promotes recovery of renal function after ischemia/reperfusion injury via anti-apoptosis and anti-inflammation (Li et al., 2016), supporting its systemic therapeutic potential.
Abstract
Molecular hydrogen has emerged as a promising therapeutic agent in respiratory medicine owing to its antioxidative, anti-inflammatory and immunomodulatory properties. Its visibility during the SARS-CoV-2 outbreak demonstrated its potential, but the significance of hydrogen therapy extends far beyond a single infection. This review examines pathological features shared across respiratory diseases, with emphasis on viral infections exemplified by SARS-CoV-2, and summarizes advances in hydrogen administration, its biological effects and therapeutic mechanisms. Particular consideration is given to biomaterial-assisted delivery strategies that enable sustained and targeted release in the lung. Clinical studies, including examples from COVID-19, provide evidence for the therapeutic potential of molecular hydrogen and its capacity to support recovery in respiratory diseases. Established administration routes such as inhalation, hydrogen-rich water and hydrogen-enriched saline have been evaluated in both preclinical and clinical settings, while emerging biomaterials provide platforms for controlled release and pulmonary targeting. Future development of hydrogen therapy in respiratory medicine is discussed, with particular focus on optimizing delivery strategies, establishing dose-effect relationships and strengthening long-term clinical evaluation.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in late 2019, rapidly escalated into a global pandemic, exposing critical vulnerabilities in existing therapeutic strategies. The virus induces profound pulmonary dysfunction, often progressing to acute respiratory distress syndrome (ARDS) characterized by diffuse alveolar damage, immune dysregulation, and inflammatory macrophage infiltration. While vaccines and antiviral drugs have been developed at unprecedented speed, their efficacy is variable and often requires early administration, leaving a therapeutic gap for patients with advanced disease or pre-existing respiratory conditions. This clinical bottleneck underscores the urgent need for adjunctive therapies that protect lung tissue, restore immune homeostasis, and improve survival beyond mere viral suppression.
Molecular hydrogen (H2) has emerged as a candidate to address this gap. Its small molecular size enables rapid diffusion to the alveoli, and its selective antioxidant and anti-inflammatory properties have been demonstrated in numerous preclinical models. However, conventional administration routes—such as inhalation or hydrogen-rich saline—suffer from limited retention and lack of targeted delivery. This review critically assesses the state of hydrogen therapy for respiratory diseases, with a focus on biomaterial-assisted delivery systems that promise sustained, lung-specific release. By synthesizing clinical and experimental evidence, we identify key parameters for effective dosing and highlight the translational hurdles that must be overcome to integrate hydrogen therapy into standard respiratory care.
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GONG Yi, QUAN Tairan, GUAN Qingqing, LI Han, TONG Jianfeng, PEI Jia (2026). Advances in Hydrogen Therapy and Hydrogen Administration Biomaterials for Respiratory Diseases. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3723-4
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Frequently Asked Questions
What is the optimal hydrogen concentration for inhalation therapy in preclinical models, and how does it translate to human dosing?
In the seminal study by Ohsawa et al. (2007), inhalation of 2% hydrogen significantly improved cerebral ischemia reperfusion injury in rats. This concentration has been widely adopted in subsequent animal studies. For human application, clinical trials have used similar or lower concentrations (e.g., 1-4% hydrogen gas) administered via nasal cannula, but dose-response relationships remain poorly defined. Establishing equivalent effective doses across species requires pharmacokinetic modeling and further clinical validation.
What are the primary mechanisms by which hydrogen exerts its therapeutic effects in respiratory viral infections?
Hydrogen acts as a selective antioxidant, neutralizing hydroxyl radicals and peroxynitrite while preserving beneficial reactive oxygen species. It also modulates inflammatory pathways, including inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokines. In the context of SARS-CoV-2, hydrogen has been shown to reduce oxidative stress and inflammation, potentially mitigating ARDS. However, the precise molecular targets and downstream signaling cascades require further elucidation.
How do biomaterial-based delivery systems improve upon conventional hydrogen administration routes?
Conventional routes such as inhalation or hydrogen-rich saline suffer from rapid clearance and lack of lung-specific targeting. Biomaterial-based systems, such as hydrogen-loaded nanoparticles or hydrogels, can provide sustained release and enhanced pulmonary retention. For example, encapsulation in biodegradable polymers allows for controlled release kinetics, potentially maintaining therapeutic hydrogen levels over extended periods. This approach may reduce dosing frequency and improve patient compliance, though scalability and biocompatibility remain challenges.
What evidence exists for the efficacy of hydrogen therapy in COVID-19 patients, and what are the limitations?
Clinical studies, including those referenced in the review, have reported that hydrogen inhalation improved oxygenation and reduced inflammation in COVID-19 patients. However, these studies are often small, non-randomized, or lack placebo controls. The review emphasizes the need for large-scale, double-blind, randomized controlled trials to establish definitive efficacy and safety. Additionally, the optimal timing and duration of hydrogen therapy in the disease course have not been standardized.
What are the key challenges in establishing dose-effect relationships for hydrogen therapy?
Hydrogen's low molecular weight and high diffusivity make it difficult to measure actual tissue concentrations. Furthermore, its effects are dose-dependent but the therapeutic window is narrow, and excessive doses may lead to adverse effects. Establishing dose-effect relationships requires development of sensitive detection methods and pharmacokinetic studies. The review calls for systematic evaluation of hydrogen concentrations, delivery routes, and exposure durations in both preclinical and clinical settings.
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