The prooxidant state and psychologic stress.

We have read with interest the work by Lesgards et al. (1) on the effect of different lifestyle factors on their test system, which measures the resistance of red blood cells to an oxidative challenge. Their study showed that psychologic stress is a major factor influencing antioxidant status. This finding encouraged us to share our experiences of a earlier study that resulted in similar conclusions using an enzyme, 5 ́-ectonucleotidase (NT), located on the external surface of lymphocytes (2,3). NT is significant because it has a role in lymphocyte maturation; newborns with persistently low activities have multiple infections, whereas with normalization of NT, their infections resolved (4). We previously showed that NT activities decreased, by then-unknown mechanism(s), as the course of HIV (human immunodeficiency virus) infection progressed (5). Later, we carried out this study in psychologically stressed patients to see if stress itself could lower the activity of this enzyme and thereby contribute to the immune deficiency reported for stressed/ depressed patients (6). In one aspect of this study, honors students in psychology were monitored at different times of the year when their stress levels were low (after holidays) and high (exams/thesis writing). These students were psychologically assessed for stress using the Profile of Mood Score (POMS). The POMS scores were significantly correlated with NT, which was significantly lower (30%) at high stress periods and normalized when the stress resolved (after holidays), indicating the reversibility of the effect of stress on NT. In another group of chronically stressed/ depressed patients, NT values were also found to be very low; however, in a subgroup of these patients taking vitamins A, C, and E and coenzyme Q10, the NT values were equivalent to those of an unstressed healthy population (2). Subsequent in vitro studies showed that NT was inhibited within 5 min after exposure to superoxide anions and that this effect could be reversed either by ascorbate added to the in vitro system at physiologic levels present in serum (100 μM) or by oral administration of the same antioxidant mix to volunteers for about 6 weeks (3,7). Measurement of tissue ascorbate also showed that this metabolite, like NT, decreased significantly at high-stress periods and resolved when the stress dissipated. Our earlier findings of low NT in HIV-positive patients further confirmed our oxidant mechanism when these patients were later shown to have a high prooxidant state (8). Besides stress, we also studied another prooxidant state—diabetes—and showed that with poor management of this condition, as measured by hemoglobin A1C (HbA1C), NT decreased significantly (7). That is, NT correlated negatively and significantly with HbA1C. These studies, taken together, confirmed that NT is a good indicator of a high prooxidant state, whether through HIV infection, psychologic stress, or diabetes. In summary, psychologic stress gives rise to a prooxidant state that is reflected by low NT and increased red blood cell sensitivity to oxidative insult. Why stress should cause a prooxidant state is not known. We hypothesize that stress by increasing cortisol favors the development of an innate immune response (2,3). In normal circumstances the innate response would abate as the adaptive immune system takes over. However, with chronic stress the high prooxidant nature of the innate response persists, because of chronically elevated cortisol, and NT and probably other important extracellular proteins of lymphocytes are inhibited, resulting in an attenuated adaptive immune response and subsequent immunodeficiency. That an innate or proinflammatory process persists in stressed patients is evidenced by persistent increased blood concentrations of acute phase proteins seen in these patients (9,10).