The Science of Ischemia-Reperfusion Injury (IRI)

Ischemia-reperfusion injury (IRI) is a complex physiological process that occurs when blood flow is restored to oxygen-deprived tissues, paradoxically causing further damage.

IRI is a major factor in organ transplant failures, post-surgical complications, and acute events like heart attacks and strokes.

Key Mechanisms of IRI

  • During reperfusion, an overabundance of reactive oxygen species (ROS), such as the hydroxyl radical (OH•), damages cellular components including DNA, proteins, lipid membranes, and mitochondria.

  • ROS triggers inflammatory cascades, releasing cytokines (e.g., TNF-α, IL-6, IL-1β) that exacerbate tissue injury.

  • Damage to biomolecules and increased inflammation lead to programmed cell death, reducing organ viability and function.

  • In transplants, IRI limits donor organ usability, increases delayed graft function, and contributes to rejection. In cardiac surgery, it raises risks of myocardial and neurological complications.

The global IRI therapeutics market was valued at $2.26 billion in 2021, projected to reach $3.15 billion by 2030, underscoring the need for effective interventions.

Diatomic HTx: A Selective and Safe Solution

Hydrogen (H₂) is a colorless, odorless gas recognized for its antioxidant properties. Unlike traditional antioxidants, H₂ offers a unique combination of safety, selectivity, and permeability, making it ideal for IRI mitigation.

Mechanism of Action

  • H₂ targets only the most harmful ROS (e.g., OH•), converting them to water without affecting beneficial species like superoxide or peroxide, which play roles in cell signaling.

  • As the smallest molecule, H₂ diffuses rapidly through biological barriers, reaching intracellular sites like mitochondria where ROS is produced.

  • H₂ modulates pathways such as NF-κB, reducing cytokine production and inflammation.

  • H₂ upregulates protective proteins (e.g., Bcl-2) and inhibits apoptosis signals (e.g., Caspase-3), preserving cell integrity.

  • H₂ is non-toxic at all dose levels, as evidenced by endogenous production of H₂ in the human gut (low dose) and by the use of 96% H₂ breathing gas in deep-sea diving applications at extreme pressures (high dose).