Antioxidant Defences Following Infection and Injury

Although pro-inflammatory cytokines are essential for the normal operation of the immune system, they play a major damaging role in many inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, asthma, psoriasis and multiple sclerosis, and in cancer (Tracey and Cerami, 1993; Grimble, 1996). They are also thought to be important in the development of atheromatous plaques in cardiovascular disease (Ross, 1993). In conditions such as cerebral malaria, meningitis and sepsis, they are produced in excessive amounts and are an important factor in increased mortality (Tracey and Cerami, 1993). Clearly, in these diseases, the cytokines are being produced in the wrong biological context. In malaria, tuberculosis, sepsis, cancer, HIV infection and rheumatoid arthritis, inflammatory cytokines bring about a loss of lean tissue, which is associated with depleted tissue GSH content and an increased output of nitrogenous and sulphur-containing excretion products in the urine (see above).

Although the body strives to maintain them, observations in experimental animals and patients indicate that antioxidant defences 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 glutathione contents of blood, respectively (Hennett et al., 1992). In asymptomatic HIV infection, substantial decreases in glutathione concentrations in blood and lung epithelial-lining fluid have been noted (Staal et al., 1992). 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 (Luo et al.,

1996). While values in blood slowly returned to pre-operative values, concentrations in muscle were still depressed 48 h post-operatively. Furthermore, reduced tissue glutathione concentration has been noted in hepatitis C, ulcerative colitis and cirrhosis. In patients with malignant melanoma, metastatic hyper-nephroma 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 (Grimble, 1999). In patients with inflammatory bowel disease, substantial reductions in ascorbic acid concentrations occurred in inflamed gut mucosa (Buffinton and Doe, 1995). As a general consequence of the weakening of antioxidant defences during disease that is attested to by these observations, oxidative damage is apparent in a wide range of clinical conditions in which cytokines are produced. Lipid peroxides and increased thiobarbituric acid reactive substances are present in the 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 haemodial-ysis. 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 (Zimmerman et al., 1989), thus illustrating the importance of GSH in protection from the adverse effects of pro-inflammatory cytokines. The onset of sepsis in patients leads to a transient decrease in the total antioxidant capacity of blood plasma (a functional measure of the total antioxidant content) (Cowley et al., 1996). The capacity returns 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 antioxidant defences also indirectly increases the risk of damage to the host via transcription-factor activation, leading to up-regulation of pro-inflammatory cytokine production (see below).

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