Reoxidation and reperfusion injury

Ischemic tissue damage after restoration of blood flow. It becomes significant after brief ischemia. If the tissue is completely damaged, reoxygenation does not have much effect on it. However, toxic substances (ROS, NO, eicosanoids) are washed out of the dead tissue into the circulation.

Tissue damage caused by toxins is MODS (multiple organ dysfunction syndrome) and SIRS (systemic inflammatory response syndrome).

Ischemic-reperfusion injury

A lack of oxygen causes a switch to anaerobic glycolysis. Reduced ATP production will cause the formation of ATP from two ADP molecules. This creates ATP and AMP. After reperfusion, AMP is removed from the body by the xanthine oxidase pathway.

The enzyme xanthine oxidase is needed to convert hypoxanthine. In humans, it is present only in the liver, intestine and lactating mammary gland. In the heart, hypoxanthine cannot be broken down (it accumulates). During the transformation, reactive forms are formed that can damage the organism (if they are not broken down quickly enough).

Conversion of AMP to uric acid.

ROS are also produced in leukocytes after reperfusion (no-flow phenomenon). Leukocytes adhere to each other and subsequently clog the capillaries. Furthermore, they arise in the mitochondria, where there is a greater leakage of electrons from complexes in the respiratory chain and as a result of MPT.

MPT (Mitochondrial permeability transition)

A megachannel in the inner mitochondrial membrane that is permeable to all molecules smaller than 1500 daltons. Its opening is conditioned by a certain amount of calcium in the mitochondrial matrix. It can also be stimulated by oxidants, depolarization and inorganic phosphate. Protons, Mg2+, ATP, ADP and cyclosporin A can inhibit MPT opening.

Physiologically, MPT serves for the beneficial efflux of calcium from mitochondria (calcium signaling). Pathologically, it induces cell death (apoptosis, necrosis), or marks old mitochondria for autophagy. By opening the MPT, the inner membrane potential collapses and the proton gradient is then equalized. Respiration will be inhibited. This is followed by swelling of the mitochondria, release of cytochrome c into the cytosol, which leads to cell apoptosis.

Reduced pH during ischemia protects against MPT.

During reperfusion in the myocardium, the conditions for MPT occur as a result of the following events:

• overproduction of oxidants
• adenine nucleotide depletion
• high concentration of Pi (from ATP degradation);
• high concentration of Ca2+
• pH normalization

During a rare MPT, it can happen that H+ go out, splitting ATP. This will lower the pH, which inhibits the formation of MPT. During reperfusion, further ATP losses occur, which worsens the condition of the cell.

Poly(ADP-ribose)-polymerase (PARP-1)

A chromatin-bound enzyme that is activated by oxidative damage to DNA. Its function is to split NAD+ and transfer poly(ADP-ribose) to nuclear proteins. Physiologically, it helps in DNA repair and promotes cell survival. Excessive DNA damage causes NAD+ depletion, which accelerates cell death. MPT also causes NAD+ depletion to some extent.

Prevention

Still not clear. Theoretically, it can be said that prevention should be controlled hypothermia, MPT inhibitors (e.g. Cyclosporin A), antioxidants and PARP-1 inhibitors.