Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress

Abstract

Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).

Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent

“…Zhou et al, who examined the radioprotective effects of H 2 on a rat skin damage model, showed that H 2 significantly reduced MDA and IL-6 levels in the damaged skin [ 52 ]. In a recent review, we reported that •OH generated in mitochondria induces oxidative stress in mitochondrial DNA (mtDNA), and that oxidized mtDNA triggers a cascade of inflammatory cytokine release from nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) to IL-1 and IL-18 [ 57 ]. The mechanism of H 2 -induced amelioration of chronic inflammatory diseases may involve the scavenging of •OH generated in mitochondria [ 57 ].…”

Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases

“…Humans have an extensive immune system by which specialized cells can combat pathogens that enter the body. In particular, inflammation is the process by which macrophages and neutrophils release proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, in direct response to this stimulus [1,[5][6][7]. Such a signal is often transient in order to trigger a quick response for the body to fight against these pathogens.…”

“…Of particular interest is the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome, which is implicated in the development of many known inflammatory diseases and commonly studied in order to inhibit the progression of chronic inflammation [8][9][10]. While the specific mechanism by which NLRP3 inflammasomes are activated is yet to be discovered, it is known that ROS play a key role in the activation step of these innate immune system receptors [1]. More specifically, ROS can oxidize mitochondrial DNA (mtDNA) that bind to NLRP3 inflammasomes in order to activate them [10].…”

“…Given that ROS are involved in the activation of NLRP3 inflammasomes, we suggested a mechanism by which oxidative stress in mitochondria can lead to this uncontrolled release of cytokines [1]. Oxidative stress is the process by which the excess production of ROS can lead to damages in the surrounding cells and tissues, including damages to mitochondria.…”

“…In a recent publication, we described the potential applications of molecular hydrogen (H 2 ) as a therapeutic agent against chronic inflammation in the body [1]. H 2 is an inert Int.…”