Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions.

The current status of superoxide dismutase (SOD) is that it is an enzyme with diverse ramifications. This review attempts an understanding of SOD as a structural, functional, and biological entity. Accordingly, the review is in three parts. The first part discusses SOD in terms of protein structure, proceeding from primary to secondary and three-dimensional structure for the three forms of SOD: copper/zinc SOD, manganese SOD, and iron SOD. This is the order of structural knowledge of the enzyme. Iron SOD is an enzyme of prokaryotes and some higher plants. Manganese SOD is an enzyme of prokaryotes and eukaryotes. Copper/zinc SOD is an enzyme of eukaryotes and certain prokaryotes. The evolutionary relationships of the three forms of SOD, the status of the copper/zinc SOD gene in prokaryotes, and the cloning and sequencing of SOD genes are discussed. The second part of the review deals with the catalytic mechanism of SOD in the three forms of the enzyme. Structural and mechanistic conclusions from various spectroscopic studies are critically considered. A detailed picture is given of the active site of copper/zinc SOD. The third part is a review of SOD in the general context of oxygen toxicity. After consideration of the question of superoxide toxicity and superoxide pathology, several areas in which SOD has been investigated or used as a tool in a biochemical, pharmacological, or clinical context are discussed, including population genetics; trisomy 21; development and senescence; the nutritional copper, zinc, and manganese status; hemolysis and anemia; oxygen toxicity in the lung and nervous system; inflammation, autoimmune disease and chromosome breakage, ischemia and degenerative changes; radiation damage; and malignancy. A comprehensive picture is given of measurements of SOD activity in disease states, and the question of superoxide-related disease is considered at several points.

Aspects of the structure, function, and applications of superoxide dismutase

Vitamin E and oxidative stress.

The intrapulmonary instillation into rat lung of enzymes that generate oxygen metabolites results in acute lung injury. The injection of xanthine oxidase and xanthine produces acute lung injury that, in the presence of superoxide dismutase, but not in the presence of catalase, can be significantly diminished, suggesting that O2- has the capacity to injure the lung. Instillation of a generator of H2O2, namely glucose oxidase, will, in sufficient quantities, produce acute injury that is not neutrophil-dependent. When either a low dose of glucose oxidase alone or lactoperoxidase alone is employed, little lung injury occurs. However, instilling the combination of the two enzymes produces severe, acute injury that can be blocked in a dose-dependent manner by catalase, but not by superoxide dismutase. Purified human leukocytic myeloperoxidase, but not horseradish peroxidase, will substitute for lactoperoxidase in the model of lung injury. The lung damaging effects of these enzymes cannot be attributed to the presence of contaminating proteases. Acute lung injury produced by the instillation of glucose oxidase and lactoperioxidase progresses to interstitial fibrosis. These studies represent a direct application of generators of oxygen metabolites to the in vivo induction of lung injury. The data suggest that rat lung is susceptible to injury by a variety of oxygen metabolites, including O2-, H2O2 and its lactoperoxidase or myeloperoxidase-produced derivatives. The studies also indicate that lung injury produced by oxygen metabolites can result in interstitial pulmonary fibrosis.

/pdf/in-vivo-damage-of-rat-lungs-by-oxygen-metabolites-20g0sa4arn.pdf

In vivo damage of rat lungs by oxygen metabolites.

Plasma extracellular superoxide dismutase (EC-SOD) from the pig, cat, rabbit, guinea pig and mouse was found to be heterogeneous with regard to heparin affinity and could be separated into three fractions: A without affinity, B with weak affinity and C with relatively high affinity. Rat plasma EC-SOD was deviant and contained only A and B fractions. There were very large interspecies differences in total plasma EC-SOD activity and in division of the activity between the different fractions. Intravenous injection of heparin resulted in the pig, dog, cat, rabbit, guinea pig and mouse in a prompt increase in the plasma SOD activity. The increase was due to release of EC-SOD C to plasma, most probably from endothelial cell surfaces. In the rat, heparin induced no increase in plasma SOD activity, apparently because of the absence of EC-SOD C in this species. The relative heparin-induced increase in plasma EC-SOD C varied between 2 and 11 in the different species and was distinctly correlated with the heparin affinity of EC-SOD C in the particular species. Apparently the EC-SOD C, present in the vasculature, forms an equilibrium between plasma and endothelium, whereas EC-SOD A and B primarily exist in plasma. The wide diversity of EC-SOD in the vascular system of mammals with regard to total amount, division into fractions and distribution between plasma and endothelium indicates that the pathogenic potential of superoxide radicals in the extracellular space might vary much between species.

Extracellular superoxide dismutase in the vascular system of mammals.

The possible role of oxygen metabolic products in immune-complex--induced injury of rat lung and of dermal blood vessels has been probed with the use of two inhibitors, superoxide dismutase (SOD) and catalase. With the use of the reversed passive Arthus reaction in the skin, local administration of SOD, but not of catalase, blocked the early phase of the tissue injury, as quantitated by the leakage of homologous albumin. The early phases of immune-complex--induced injury of the lung were completely blocked by the parenteral (intraperitoneal) administration of SOD. Except at very high doses, SOD did not interfere with chemotactic-factor--induced release of lysosomal enzymes from rat neutrophils. These data suggest that oxygen metabolic products such as O(2-) may play an important role in the early phases of damage produced in rat alveolar walls and dermal vasculature by the deposition of immune complexes.

Suppression by superoxide dismutase of immune-complex--induced pulmonary alveolitis and dermal inflammation.

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Suppression by superoxide dismutase of immune-complex--induced pulmonary alveolitis and dermal inflammation.