The term “oxidation” refers to the loss of electrons and “reduction” refers to the gain of electrons, as shown in Fig. 13.1.

The oxidation of iron is an example of a redox reaction. When iron is oxidized by oxygen, iron oxide results, which is known as “rust.” An example is the formation of rust in the cornea when a foreign body sticks in the cornea (Fig. 13.2).

Besides the formation of iron oxide, iron can also be oxidized by transferring electrons to hydrogen peroxide in the so-called Fenton reaction, thereby creating reactive oxygen species (ROS) (Fig. 13.3).

Pro-oxidants are molecules that can oxidize other molecules; in other words, they have an oxidizing potential that is stronger than the oxidizing potential of the molecule they react with. A small but pathophysiologically important subgroup of prooxidants is reactive oxygen species (ROS). ROS shall subsequently be discussed in more detail.

ROS are oxygen-containing molecules that are highly reactive. ROS can occur in the form of free radicals (e.g., superoxide anion) or non-radical species (e.g., singlet oxygen). Free radicals are molecules that contain one or more unpaired ­electrons. The presence of an unpaired electron makes free radicals highly reactive because of the need to pair up the unpaired electron.

The normally occurring oxygen molecule in the atmosphere is relatively inert and called “ground-state oxygen” (Fig. 13.4) due to the fact that the unpaired electrons in the oxygen molecule have the same spin (refer to Chap. 9). Thus, for the oxygen molecule to react, it would need another molecule or atom with two unpaired electrons with a parallel spin opposite to that of the oxygen molecule. This rarely occurs, which explains why oxygen in the ground state is only minimally reactive.

The activation of ground-state oxygen may occur by two different mechanisms: either through the absorption of sufficient energy to reverse the spin on one of the unpaired electrons or through monovalent reduction. If ground-state oxygen absorbs sufficient energy to reverse the spin of one of its unpaired electrons, the two unpaired electrons now have opposite spins (see Sect. 9.5). Due to a change in spin direction, this oxygen molecule, called singlet oxygen (¹O₂), is much more reactive than ground-state oxygen and reacts destructively, particularly with molecules with double bonds.

The second mechanism of activation is by the stepwise monovalent reduction of oxygen, which gives rise to the superoxide anion radical (O₂⁻) (Fig. 13.5), hydrogen peroxide (H₂O₂), and, finally, to water (H₂O).

Both of these mechanisms also occur in our bodies. The production of singlet oxygen is of particular importance in organs exposed to light, such as the eye and the skin, whereas the production of superoxide anion occurs essentially in any tissue. In aerobic cells, energy is gained by oxidizing molecules such as sugar. During this energy metabolism, a certain amount of ROS is produced physiologically as a byproduct. This occurs mainly during electron transfer in the respiratory chain. The tetravalent reduction of molecular oxygen (together with hydrogen) by the mitochondrial electron–transport chain produces water. This system, however, does not always work perfectly and, as a result of electron leakage, the univalent reduction of oxygen molecule forms superoxide anions (O₂⁻). ROS can also be built as intermediates in enzymatic ­reactions. Certain cell types such as macrophages can produce high amounts of ROS as a part of their defense mechanism (Fig. 13.6).

ROS production is obviously not only detrimental but can also be beneficial. It is, for example, a prerequisite to achieve the optimal physical training effect. However, an unwanted increase in ROS occurs in a number of pathologic conditions such as those resulting from an unstable oxygen supply. This is particularly relevant in elderly people, as the capacity to eliminate free radicals decreases with age (Fig. 13.7). Under optimal conditions, the magnitude of ROS formation is balanced by the rate of ROS elimination through the available antioxidants. If the production of ROS exceeds the capacity of its elimination, the amount of ROS increases to a level that leads to oxidative stress. This condition is described in greater detail below.

Nature has provided us with mechanisms to cope with ROS with the help of antioxidants. An antioxidant, by definition, is any substance that reduces oxidative damage, such as that caused by free radicals. The ­antioxidant defense system is comprised of a variety of molecules. These include proteins such as enzymes (e.g., superoxide dismutase and catalase) and low-molecular mass molecules (e.g., some vitamins).

Oxidative stress can damage molecules. One example is lipid degradation initiated by lipid peroxidation (Fig. 13.8). This is a process by which molecular oxygen (O₂) is inserted into an unsaturated fatty acid (called a lipid peroxide). This process is initiated by free radicals. The formation of peroxide again leads to the formation of free radicals, inducing a chain reaction.

As long as nature is capable of repairing damaged molecules (e.g., DNA) or eliminating them (e.g., proteins via proteosomes), no major structural damage will occur. However, if oxidative stress exceeds the capacity of antioxidants and the molecular damage exceeds the capacity of repair or elimination mechanisms, structural damage will occur. This results in damage that is ultimately clinically relevant as a basis of diseases (Fig. 13.9). This can occur in any organ, including the eye. In this context, we will focus on eye diseases.

The cornea and the conjunctiva are in direct contact with the ambient air. This has a positive effect on the cornea, as it can receive its oxygen supply from the air, but it also has a negative effect, as the cornea and the conjunctiva are exposed to toxic substances such as ozone in the air. Likewise, the retina requires light for vision but light can also contribute to the production of ROS via photodynamic procedures. We will now discuss some of the consequences of oxidative stress in the eye.

Oxidative stress plays a role in the pathogenesis of cataract formation (Fig. 13.10).

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