OXIDATIVE STRESS AND DISEASE/chronic infections

Oxidative Stress

REACTIVE OXYGEN SPECIES AND OXIDATIVE STRESS

Oxidative stress results from the damaging action of reactive oxygen species. These molecules react with proteins, lipids or DNA, altering their structure and causing oxidative damage to the cells.

Reactive oxygen species (ROS) are produced during normal physiological processes such as energy production, which inevitably leads to the generation of oxidative molecules: superoxide (O₂^._), hydrogen peroxide (H₂O₂) or hydroxyl radical (^.OH). Transition metals like Fe or Cu, although required for certain enzymatic functions, exacerbate oxidative damage by catalyzing the conversion of hydrogen peroxide into ^.OH, a highly reactive radical that will immediately react with any biological molecule, notably poly-unsaturated fatty acids.

Another important free radical is nitric oxide (NO). This molecule, produced by the iNOS and eNOS enzymes, exerts various physiologic functions as a neuromediator, regulator of immune functions, or vasodilator. However, it can react with superoxide to form peroxynitrite (ONOO-), an extremely potent cellular oxidant.

ANTIOXIDANT PATHWAYS

To a certain extent, our cells can protect themselves against oxidative damage. The enzyme superoxide dismutase (SOD) catalyzes the dismutation of superoxide to H₂O₂, which is then converted to H₂O by gluthatione peroxidase (GPx) or to O₂ + H₂O by catalase. The reaction catalyzed by GPx requires gluthatione (GSH), which is converted to reduced gluthatione (GSSG). The concentrations of GSH and GSSG, and their ratio, reflect the redox state of the cell and are crucial for an efficient ROS detoxification.

The detrimental effect of transition metals is minimized through the action of proteins like ferritin, transferrin, lactoferrin that can store Fe ions, keeping their free cellular concentration as low as possible.

Finally, cells are also protected by radical-scavenging antioxidants such as vitamin E that can capture free radicals.

IN CERTAIN SITUATIONS OUR CAPACITY TO FIGHT AGAINST OXIDATIVE STRESS CAN BE ALTERED

Factors that influence the efficiency of antioxidant defense are the following:

• Nutritional deficiencies: adequate nutritional intake is crucial. Antioxidant systems require a variety of cofactors (glutathione, sulfate, vitamin A, vitamin E, or minerals like selenium and copper) that should be present in our food. Proper fatty acid supplementation is also determinant, since it could compensate for the damage caused by oxidative stress (poly-unsaturated fatty-acids are very sensitive to oxidative damage).
• Exposure to toxic chemicals: excessive exposure to toxic chemicals present in our environment can cause severe oxidative damage. For instance, dioxin increases the production of reactive oxygen species by the mitochondria, leading to oxidative damage in the endothelium, liver and brain. Exposure to certain chlorinated compounds is associated with an increase of 8-OhdG, a marker of DNA oxidative damage. Organophosphate pesticides generate free radicals and alter the antioxidant defense system in erythrocytes. Heavy metal exposure also causes strong oxidative damage: mercury, lead, cadmium, arsenic promote the formation of hydrogen peroxide and at the same time inhibit anti-oxidant enzymes (GSH synthetase, GSH reductase, SOD). Since most chemicals can to some extent generate oxidative stress, exposure to low doses of different chemicals may finally, when they combine, lead to a significant oxidative burden.
• Infections: infections and inflammatory processes are associated with production of pro-oxidative molecules. Phagocytic cells indeed kill bacteria by producing hypochlorous acid (HOCl) from hydrogen peroxide (a reaction catalyzed by myeloperoxidase). Hypochlorous acid is itself a strong oxidant. Chronic infections are therefore associated with increased oxidative burden; for instance, Helicobacter pylori infections cause severe oxidative damage to the gastric mucosa.

OXIDATIVE STRESS AND DISEASE

Oxidative stress is implicated in a large number of diseases: cancer (oxidative damage to DNA causes mutations that can lead to carcinogenesis), atherosclerosis (atherosclerotic plaques are made from oxidized fat), neuro-degenerative diseases (oxidative damage is a central component of nerve cell destruction). Indicators of oxidative stress have been detected in muscles and blood of CFS patients. Oxidative damage can alter the blood-brain barrier, which could explain some of the cognitive problems experienced by patients.