The oxygen paradox is the dichotomy between the essential need for oxygen and the toxicity of this compound. As a result of the utilization of oxygen during respiration or during inflammation produces a series of reactive oxygen species (ROS) including superoxide (O2-.), hydrogen peroxide (H2O2); hydroxyl radical (HO.), lipid peroxides (LOOH), nitric oxide (NO) and hypochlorous acid (HOCl). Neutrophils and macrophages produce ROS during the respiratory burst to kill microorganisms but, because of the high reactivity, the ROS injure bystander cells of the host. The generation of ROS is termed oxidative stress and is a mechanism of cell injury in a variety of conditions. ROS are important in many physiological functions but it is well recognized that balance between the oxygen utilization, ROS formation and anti-oxidant activity is essential for normal function.
This paper describes a new possible role for ROS as a mediator of apoptosis. More specifically, the authors demonstrated that ROS may be responsible for apoptosis of lymphocytes in HIV infected patients and thus produce the severe loss of these immune cells seen in such patients.
Mononuclear cells from HIV patients and from normals were stimulated by co-incubation with E. coli. Cells from the HIV patients produced more ROS than those from healthy controls. Consequently, there was an increase in apoptosis when compared to controls. Anti-oxidant treatment with glutathione (GSH), N-acetylcysteine (NAC) and catalase inhibited apoptosis which is in accordance with the hypothesis. In contrast, treatment with super-oxide dismutase (SOD), which is also considered an anti-oxidant enzyme, produced a marked increase in apoptosis.
Apoptosis was also studied in the presence of anti-TNFà antibody and in a cell free system (hypoxyxanthine and xanthine oxidase). The former had no effect, whereas the cell free ROS producing system showed the same pattern of responses to anti-oxidant treatment. These data demonstrated that the effects were not due to TNFà_or other soluble, cell derived factors.
The effect of SOD appeared to be anomalous given that all other anti-oxidant treatments produced a decrease in apoptosis. SOD however, converts O2 -. to H202 and cell membranes are permeable to the latter but not the former ROS. If catalase, which converts peroxide to water, was added, both the intracellular H202 concentrations and the degree of apoptosis were reduced. This confirmed the hypothesis that permeability of the cell membrane was an important determinant of ROS mediated apoptosis.
Apoptosis in lymphocytes from healthy and HIV infected individuals increased upon being subjected to ROS. This effect was reduced in the presence of anti-oxidants. Within the sub-groups, there is a similar degree of apoptosis with CD3+, CD4+ and CD8+; all demonstrated a similar increase in cell death when exposed to ROS. As expected, CD14+ monocytes which are phagocytic cells and contain high titres of anti-oxidant activity are not affected by ROS production. Cells from HIV patients demonstrated a greater degree of apoptosis when treated with ROS producing systems. This effect was observed even in very early stages of infection with cells from asymptomatic patients.
The role of ROS is usually considered as a toxin used in the killing of micro-organisms or other foreign tissue. In auto-immune disease, it is believed to be responsible for the tissue damage seen in such conditions as arthritis. This paper demonstrates that it may also be involved in a developmental process such as apoptosis. The paper also demonstrates that cell death in AIDS may not be totally attributable to soluble factors such as TNFà. The possible role of ROS gives support to the contentious hypothesis that diet may be a useful therapeutic adjunct. It also targets the very early stages of HIV infection as an important therapeutic window.
On the level of molecular events, the paper demonstrates the different activities of ROS and the enzymes used to control these toxic compounds. It is counter-intuitive that SOD, an anti-oxidant enzyme enhances the activity from ROS. The demonstration that H202, the product from dismutation of superoxide, penetrates the cell membrane is important for investigators studying oxygen toxicity. It is necessary to account for all species formed and to consider their localization in the cell.
Programmed cell death (apoptosis) of T-Iymphocytes observed in human immunodeficiency virus (HIV) infected individuals could be linked to oxidative stress. Therefore, we have investigated whether reactive oxygen species (ROS) induce apoptosis, which might contribute to the cell loss during progression of HIV-1 infection. ROS were generated in peripheral blood mononuclear cells (PBMC) obtained from HIV-1-positive patients and from healthy controls by stimulation with bacteria or by treatment with hypoxanthine/xanthine oxidase, which has been shown to generate ROS without direct involvement of cytokines. A dose-dependent inhibition of ROS formation correlated with the reduction of apoptosis induced by both bacterial and hypoxanthine/xanthine oxidase stimulation, suggesting that ROS generation was responsible for the induction of apoptosis. In addition, hydrogen peroxide (H202) rather than superoxide (02) was observed to induce apoptosis. ROS-dependent apoptosis was shown to be independent of cytokines such as tumor necrosis factor-à (TNF-à). ROS-induced apoptosis was significandy enhanced in HIV-infected subjects even in the very early stages after infection. Moreover, ROS-mediated apoptosis was not restricted to a particular lymphocyte subset. In view of the diminished oxidative resistance of HIV-infected individuals, our results suggest that ROS-mediated apoptosis might contribute to the deletion of lymphocytes and to the pathogenesis of the disease.
This is hot topic. I have taken the liberty of listing a few reviews relating to apoptosis and free radicals to indicate the diverse interests in this area. Of course, some of these reviews may be of more interest to you than others.
Gaulding, 1997
Angiotensin II signaling in vascular smooth muscle
Hypertension 29:365-377
Jenner P, 1996
Oxidative stress and the pathogenesis of Parkinson's disease.
Neurology 47(6), S161-S170 (1996)
McConkey DJ, 1996
Signal transduction pathways in apoptosis.
Cells 14(6), 619-631 (1996)
Gorman AM, 1996
Oxidative stress and apoptosis in neurodegeneration.
J Neurol Sci 139, 45-52 (1996)
Korsmeyer SJ, 1995
Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family.
Biochim. Biophys. Acta 1271(1), 63-66 (1995)
Slater AF, 1995
The role of intracellular oxidants in apoptosis.
Biochim. Biophys. Acta 1271(1), 59-62 (1995)