Physiology in medicine
Phagocytes and oxidative stress

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Abstract

Neutrophils and other phagocytes manufacture O2 (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O2 reacts with itself to form H2O2 (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl by H2O2; OH· (hydroxyl radical), produced by the reduction of H2O2 by Fe++ or Cu+; ONOO (peroxynitrite), formed by the reaction between O2 and NO·; and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.

Section snippets

A short history of oxidants and phagocytes

The role of phagocytes in host defense was discovered late in the nineteenth century by Elie Metchnikoff (1), who noted that these cells crowded around sharp thorns with which he had pierced transparent starfish larvae. Metchnikoff concluded that these “wandering cells,” as he called them, were somehow involved in defending the starfish larvae against the damage inflicted by the thorns. The following 50 years saw a protracted war between those who said that host defense was the responsibility

The enzymes

Phagocytes manufacture a stupendous battery of reactive oxidants that they use for the destruction of invading microorganisms. These oxidants are generated by four enzymes: NADPH oxidase, superoxide dismutase, nitric oxide synthase, and myeloperoxidase (in the case of eosinophils, eosinophil peroxidase).

The oxidants

The actions of the enzymes described above give rise to four products: O2, H2O2, NO, and HOCl. All the myriad oxidants produced by phagocytes arise from nonenzymatic reactions involving those four compounds (Figure 3).

Emphysema

Neutrophils contain three neutral proteases, cathepsin G, elastase, and proteinase 3, which reside in their azurophil granules. They are called neutral proteases because, unlike lysosomal proteases, which are most active in acidic environments, these proteases operate best at neutral pH, that is, the pH of normal tissues. These proteases are employed chiefly to degrade substances that neutrophils have ingested, but because the contents of azurophil granules are sometimes released into the

Conclusion

It is clear from the foregoing that reactive oxidizing species produced from phagocytes are important in the pathogenesis of many conditions. It may be that the development of drugs to antagonize these oxidizing species can prevent at least some of the damage inflicted on tissues by these very reactive agents. (Figure 8)

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    Supported in part by USPHS Grants AI-24227, AI-28479, and AI-44434.

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