Molecular hydrogen is a promising therapeutic agent for pulmonary disease

ABSTRACT

1. INTRODUCTION

Molecular hydrogen is a colorless, odorless, and tasteless gas molecule with poor water solubility. It is considered inert in mammalian cells under physiological conditions. Molecular hydrogen can be broken down by some bacteria via enzymatic catalysis to provide energy and electrons. In addition, bacteria produce molecular hydrogen by anaerobic metabolism. Genes encoding the iron- or nickel-containing enzymes necessary to catalyze these reactions, such as hydrogenase, are lacking in mammals (Fritsch et al., 2013). However, molecular hydrogen is now recognized as a novel medically relevant gas with therapeutic potential. Ohsawa et al. (2007) reported that the inhalation of 2% molecular hydrogen results in the selective scavenging of hydroxyl free radical (·OH) and peroxynitrite anion (ONOO-), significantly improving oxidative stress injury caused by cerebral ischemia/reperfusion (I/R). This study prompted substantial interest in the medical value of molecular hydrogen, and many cellular, animal, and clinical trials and studies have since investigated its preventive and therapeutic effects. Molecular hydrogen can exert biological effects on almost all organs, including the brain, heart, lung, liver, and pancreas. It has a variety of biological functions, including roles in the regulation of oxidative stress and anti-inflammatory and anti-apoptotic effects (Iketani and Ohsawa, 2017; Kura et al., 2019; Hu et al., 2020; Kawamura T et al., 2020).

The lungs are the primary organ for gas exchange between the surrounding environment and the circulatory system. During respiration, they are constantly exposed to various environmental irritants, such as bacteria, viruses, and other pathogens, and to other harmful external stimuli, such as tobacco smoke and airborne particulate matter. Short- or long-term exposure to these harmful substances often results in lung injury, causing respiratory and lung diseases (Bhattacharya and Matthay, 2013). Acute and chronic respiratory diseases have high rates of morbidity and mortality, and the efficacy of treatment strategies is insufficient, making these diseases a major public health concern worldwide (Bhattacharya and Matthay, 2013). For example, coronavirus disease 2019 (COVID-19), a form of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely, resulting in an ongoing pandemic.

This review is based on publications up to May 2021 which were retrieved by a selective search in the PubMed database, and includes clinical trials, animal studies, and reviews. The search terms included "hydrogen," "acute lung injury (ALI)," "chronic obstructive pulmonary disease (COPD)," "asthma," "cancer," "pulmonary arterial hypertension (PAH)," "pulmonary fibrosis (PF)," and "hydrogen." We briefly discuss the mechanism of action of molecular hydrogen and its effects on biological functions and cellular processes. We then describe the status of research on its contributions to various lung diseases. We expect molecular hydrogen to have an increasing role in the treatment and prevention of lung diseases. This review provides support for the development of future treatments based on molecular hydrogen.