The use of transgenic mice to evaluate the role of overexpression of human antioxidants in chemically and physiologically induced models of oxidative stress.

摘要

Reactive oxygen species (ROS) are ubiquitous, highly reactive molecules which exist under normal and pathological states in almost all organisms. These molecules may be deleterious if they are produced in excess or if allowed to accumulate within the cell. Most cells possess natural defenses comprised of enzymatic and non-enzymatic antioxidants; however, under certain conditions the ROS may overwhelm these host defenses and cause damage to cell macromolecules because of their high reactivity. Alternatively, ROS may incur damage by interfering with normal cell signaling or inducing expression of harmful or lethal genes. In fact, ROS have been associated with a large number of serious human diseases such as atherosclerosis, stroke and diabetes. Investigations into the precise roles and efficiency of different antioxidant enzymes in treatment of disease is of primary importance.; Transgenic mice overexpressing human antioxidant enzymes (intracellular or extracellular form of human glutathione peroxidase (GP) and superoxide dismutase (SOD))) were used to investigate the effects of increased levels of GP and SOD on oxidative insult in two different models of human disease. The first model entails the use of a chemical toxicant--acetaminophen, and the second involves ischemia/reperfusion (I/R) injury. In these studies, parameters of oxidative stress as well as functional and histological analyses of target organs were evaluated. Overexpression of extracellular GP (GPP) protected experimental animals against acetaminophen toxicity according to biochemical, histological and behavioral criteria. In contrast, overexpression of intracellular GP (GPE) caused sensitization of these animals as compared to nontransgenics. Focal cerebral ischemia was induced through intraluminal blockade of the middle cerebral artery. Renal ischemia was achieved through temporary occlusion of the renal artery. In both stroke and kidney models of I/R, GPE animals were significantly protected against histologic and functional damage, whereas in the renal model GPP mice sustained enhanced injury as compared to nontransgenic animals. In conclusion, the involvement of reactive oxygen species has been demonstrated in models of acetaminophen toxicity and ischemia/reperfusion in the kidney and brain. The level of activity of antioxidant enzymes is able to influence the outcome in these models, and different types or localizations of these enzymes result in significantly different effects on outcome. Finally, the ability of these enzymes to impact on chemical toxicity and I/R damage suggests therapeutic application of these antioxidants.