Acute Stressinduced Changes in Blood Leukocyte Numbers Contradicting Results or a Biphasic Response

As stated before, stress has been shown to induce a significant decrease in blood leukocyte numbers in a range of different species. However, studies have also shown that stress can increase rather than decrease blood leukocyte numbers in humans (Naliboff et al., 1991; Schedlowski et al., 1993a; Brosschot et al., 1994; Mills et al., 1995; Bosch et al., 2003). This apparent contradiction is resolved when three important factors are taken into account: first, stress-induced increases in blood leukocyte numbers are observed after stress conditions that primarily result in the activation of the sympathetic nervous system. These stressors are often of a short duration (few minutes) or relatively mild (e.g., public speaking) (Naliboff et al., 1991; Schedlowski et al., 1993a; Brosschot et al., 1994; Mills et al., 1995). Second, the increase in leukocyte numbers may be accounted for by stress- or catecholamine-induced increases in granulocytes and NK cells (Naliboff et al., 1991; Schedlowski et al., 1993a; Brosschot et al., 1994; Mills et al., 1995; Benschop et al., 1996). Because granulocytes form a large proportion of circulating leukocytes in humans (60-80% granulocytes), an increase in gran-ulocyte numbers is reflected as an increase in total leukocyte numbers in contrast with rats and mice (10-20% granulocytes). Third, stress or pharmacologically induced increases in glucocorticoid hormones induce a significant decrease in blood lymphocyte and monocyte numbers (Hoagland et al., 1946; Stein et al. ,1951; Schedlowski et al., 1993a; Dhabhar et al., 1996). Thus, stress conditions that result in a significant and sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis will result in a decrease in blood leukocyte numbers.

In view of the above discussion, it may be proposed that acute stress induces an initial increase followed by a decrease in blood leukocyte numbers. Stress conditions that result in activation of the sympathetic nervous system, especially conditions that induce high levels of norepi-nephrine, may induce an increase in circulating leukocyte numbers. These conditions may occur during the very beginning of a stress response, very short duration stress (order of minutes), mild psychological stress, or during exercise. In contrast, stress conditions that result in the activation of the HPA axis induce a decrease in circulating leukocyte numbers. These conditions often occur during the later stages of a stress response, long-duration acute stressors (order of hours), or during severe psychological, physical, or physiological stress. An elegant and interesting example in support of this hypothesis comes from Schedlowski et al. who measured changes in blood T cell and NK cell numbers as well as plasma catecholamine and cortisol levels in parachutists (Schedlowski et al., 1993a). Measurements were made 2h before, immediately after, and 1h after the jump. Results showed a significant increase in T cell and NK cell numbers immediately (minutes) after the jump that was followed by a significant decrease 1 h after the jump. An early increase in plasma catecholamines preceded early increases in lymphocyte numbers, whereas the more delayed rise in plasma cortisol preceded the late decrease in lymphocyte numbers (Schedlowski et al., 1993a). Importantly, changes in NK cell activity and antibody-dependent cell-mediated cytotoxicity closely paralleled changes in blood NK cell numbers, thus suggesting that changes in leukocyte numbers may be an important mediator of apparent changes in leukocyte "activity." Similarly, Rinner et al. have shown that a short stressor (1-min handling) induced an increase in mitogen-induced proliferation of T and B cells obtained from peripheral blood, whereas a longer stressor (2-h immobilization) induced a decrease in the same proliferative responses (Rinner et al., 1992). In another example, Manuck et al. showed that acute psychological stress induced a significant increase in blood Cytolytic T Lymphocyte (CTL) numbers only in those subjects who showed heightened catecholamine and cardiovascular reactions to stress (Manuck et al., 1991).

Thus, an acute stress response may induce biphasic changes in blood leukocyte numbers. Soon after the beginning of stress (order of minutes) or during mild acute stress or exercise, catecholamine hormones and neu-rotransmitters induce the body's "soldiers" (leukocytes) to exit their "barracks" (spleen, lung, marginated pool, and other organs) and enter the "boulevards" (blood vessels and lymphatics). This results in an increase in blood leukocyte numbers, the effect being most prominent for NK cells and granulocytes. As the stress response continues, activation of the HPA axis results in the release of glucocorticoid hormones that induce leukocytes to exit the blood and take position at potential "battle stations" (skin, mucosal lining of gastrointestinal and urinary-genital tracts, lung, liver, and lymph nodes) in preparation for immune challenges that may be imposed by the actions of the stressor (Dhabhar et al., 1995a; Dhabhar and McEwen, 1996, 2001). Such a redistribution of leukocytes results in a decrease in blood leukocyte numbers, the effect being most prominent for T and B lymphocytes, NK cells, and monocytes. Thus, acute stress may result in a redistribution of leukocytes from the barracks, through the boulevards, and to potential battle stations within the body.

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