Decline In Antioxidant Defenses And Increased Oxidant Damage Follows Infection And Injury

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There is a growing body of evidence that anti-oxidants suppress inflammatory components of the response to infection and trauma and enhance components related to cell-mediated immunity. The reverse situation applies when anti-oxidant defenses become depleted.

Although the body strives to maintain them, observations in experimental animals and patients indicate that anti-oxidant defenses become depleted during infection and after injury. For example, in mice infected with influenza virus, there were 27%, 42%, and 45% decreases in the vitamin C, vitamin E, and glu-tathione contents of blood, respectively (13). In a further study on mice, given a dose of endotoxin sufficient to cause septic shock, both GSH and ascorbic acid were shown to fall precipitately in spleen, lymph nodes, and peritoneal macrophages (14). In asymptomatic HIV infection, substantial decreases in glutathione concentrations in blood and lung epithelial lining fluid have been noted (15). In patients undergoing elective abdominal operations, the glutathione content of blood and skeletal muscle fell by over 10% and 42%, respectively, within 24 h of the operation (16). Blood concentrations returned rapidly to preoperative values; however, concentrations in muscle were still depressed 48 h after the operations. A diverse range of clinical treatments and diseases, all of which involve the inflammatory process, have been shown to lead to a decrease in tissue anti-oxidant concentrations. These include hepatitis C, ulcerative colitis, and cirrhosis. In patients with malignant melanoma, metastatic hypernephroma, and metastatic colon cancer, plasma ascorbic acid concentrations fell from normal to almost undetectable levels within 5 days of commencement of treatment with IL-2 (17). In patients with inflammatory bowel disease, substantial reductions in ascorbic acid concentrations occurred in inflamed gut mucosa (18). As a general consequence of the weakening of anti-oxidant defenses, during disease, oxidative damage is apparent in a wide range of clinical conditions in which cytokines are produced. Lipid peroxides and increased thiobar-bituric acid reactive substances are present in blood of patients with septic shock, asymptomatic HIV infection, chronic hepatitis C, breast cancer, cystic fibrosis, diabetes mellitus, and alcoholic liver disease. Peroxides also increase following cancer chemotherapy, open heart surgery, bone marrow transplantation, and hemodialysis (17).

There is evidence, from studies on experimental animals and patients, that the decrease in strength of anti-oxidant defenses may exert a deleterious influence. When glutathione status was reduced in rats by injection of diethyl maleate, which binds irreversibly to GSH rendering it inactive, a sublethal dose of TNF became lethal (19), thus illustrating the importance of GSH in protection from the adverse effects of pro-inflammatory cytokines. A parallel phenomenon was noted in patients with sepsis. The onset of sepsis in patients led to a transient decrease in the total anti-oxidant capacity of blood plasma (a functional measure of the total anti-oxidant content) (20). The capacity returned to normal values over the following 5 days. However, this was not the case for patients who subsequently died, in whom values remained well below the normal range.

As well as increasing the risk of direct oxidant damage, a reduction in the strength of anti-oxidant defenses also indirectly increases the risk of damage to the host via transcription factor activation leading to upregulation of pro-inflammatory cytokine production (see later).

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