Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.

Role of reactive oxygen species (ROS) in apoptosis induction

Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, β-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the...

Exercise and the Immune System: Regulation, Integration, and Adaptation

Exercise-induced muscle injury in humans frequently occurs after unaccustomed exercise, particularly if the exercise involves a large amount of eccentric (muscle lengthening) contractions. Direct measures of exercise-induced muscle damage include cellular and subcellular disturbances, particularly Z-line streaming. Several indirectly assessed markers of muscle damage after exercise include increases in T2 signal intensity via magnetic resonance imaging techniques, prolonged decreases in force production measured during both voluntary and electrically stimulated contractions (particularly at low stimulation frequencies), increases in inflammatory markers both within the injured muscle and in the blood, increased appearance of muscle proteins in the blood, and muscular soreness. Although the exact mechanisms to explain these changes have not been delineated, the initial injury is ascribed to mechanical disruption of the fiber, and subsequent damage is linked to inflammatory processes and to changes in excitation-contraction coupling within the muscle. Performance of one bout of eccentric exercise induces an adaptation such that the muscle is less vulnerable to a subsequent bout of eccentric exercise. Although several theories have been proposed to explain this "repeated bout effect," including altered motor unit recruitment, an increase in sarcomeres in series, a blunted inflammatory response, and a reduction in stress-susceptible fibers, there is no general agreement as to its cause. In addition, there is controversy concerning the presence of sex differences in the response of muscle to damage-inducing exercise. In contrast to the animal literature, which clearly shows that females experience less damage than males, research using human studies suggests that there is either no difference between men and women or that women are more prone to exercise-induced muscle damage than are men.

Exercise-induced muscle damage in humans.

An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies.

Position statement. Part one: Immune function and exercise.

Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes

Neutrophils play important roles in host defense against all classes of infectious agents but, para- doxically, they are also involved in the pathology of van- ous inflammatory conditions. Their microbicidal armory consists of oxidative and nonoxidative processes that are activated simultaneously upon phagocytosis. Although destruction of infectious agents occurs intracellulanly, release of cytotoxic molecules into the extracellulan milieu can damage body tissues. Neutrophils are heterogeneous. Subpopulations exist in various stages from dormant to primed to fully activated. The activities of neutrophils are regulated locally in microenvironments and systemi- cally by a plethora of mediators including cytokines, "classical" neuroendocrine hormones, and bioactive lipids. The net response depends on a complex balance of stimulatory and inhibitory pathways that are regulated by these mediators. Although some effector and regula- tory pathways are vital, considerable redundancy is also evident. Identification of the essential mediators and the unraveling of any interactions may be the keys to under- standing the neutrophil paradox and developing then- apeutic strategies that optimize microbial killing and minimize host tissue damage. Finally, reports that neu- trophils can act as drug delivery vectors and that their function is influenced by stress and other lifestyle factors suggest that new homeostatic functions for these cells, outside their traditional roles in host defense and inflam- mation, remain to be identified: some are speculated on here.J. Leukoc. Biol. 56: 672-686; 1994.

Neutrophils, host defense, and inflammation: a double-edged sword.

There is a wide body of literature reporting red cell hemolysis as occurring after various forms of exercise. Whereas the trauma associated with footstrike is thought to be the major cause of hemol...

Footstrike is the major cause of hemolysis during running

Endurance training can lead to what has been termed ‘sports anaemia’ Although under normal conditions, red blood cells (RBCs) have a lifespan of about 120 days, the rate of aging may increase during intensive training However, RBC deficiency is rare in athletes, and sports anaemia is probably due to an expanded plasma volume Cycling, running and swimming have been shown to cause RBC damage While most investigators measure indices of haemolysis (for example, plasma haemoglobin or haptoglobin), RBC removal is normally an extravascular process that does not involve haemolysis Attention is now turning to cellular indices (such as antioxidant depletion, or protein or lipid damage) that may be more indicative of exercise-induced damage RBCs are vulnerable to oxidative damage because of their continuous exposure to oxygen and their high concentrations of polyunsaturated fatty acids and haem iron As oxidative stress may be proportional to oxygen uptake, it is not surprising that antioxidants in muscle, liver and RBCs can be depleted during exercise Oxidative damage to RBCs can also perturb ionic homeostasis and facilitate cellular dehydration These changes impair RBC deformability which can, in turn, impede the passage of RBCs through the microcirculation This may lead to hypoxia in working muscle during single episodes of exercise and possibly an increased rate of RBC destruction with long term exercise Providing RBC destruction does not exceed the rate of RBC production, no detrimental effect to athletic performance should occur An increased rate of RBC turnover may be advantageous because young cells are more efficient in transporting oxygen Because most techniques examine the RBC population as a whole, more sophisticated methods which analyse cells individually are required to determine the mechanisms involved in exercise-induced damage of RBCs

Exercise, Training and Red Blood Cell Turnover

The concentration in human plasma of putative neutrophil-"priming" cytokines like endogenous pyrogens is known to increase significantly in response to moderate exercise (11). This is characteristic of an acute-phase response. The ability of blood neutrophils isolated from both trained and untrained human subjects (n = 11, 9) to produce microbicidal reactive oxygen species was determined using luminol-enhanced chemiluminescence both before and after one hour of aerobic exercise at 60% VO2max. Irrespective of training and stimulus concentration, exercise nearly always caused significant "priming" of the capacity of neutrophils to produce H2O2 and HOCl upon stimulation with opsonized zymosan (P less than 0.01); however, compared to their untrained counterparts, the activity of cells isolated from trained individuals was depressed about 50% at unit stimulus concentration, both before and after exercise (P less than 0.075), whilst remaining unaltered at saturating concentrations. Although neutrophil oxygenation activity is only one parameter that contributes to immunological status, regular episodes of moderate exercise may increase resistance to infection by priming the "killing capacity" of neutrophils. In contrast, prolonged periods of intensive training may lead to increased susceptibility to common infections by diminishing this activity.

John A. Smith

Papers

Neutrophils, host defense, and inflammation: a double-edged sword.

Footstrike is the major cause of hemolysis during running

Exercise, Training and Red Blood Cell Turnover

Exercise, training and neutrophil microbicidal activity.

Further characterization of the neutrophil oxidative burst by flow cytometry.