Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Strenuous exercise increases oxygen consumption and causes disturbance of intracellular pro-oxidant-antioxidant homeostasis. The mitochondrial electron transport chain, polymorphoneutrophil, and xanthine oxidase have been identified as major sources of intracellular free radical generation during exercise. Reactive oxygen species pose a serious threat to the cellular antioxidant defense system, such as diminished reserve of antioxidant vitamins and glutathione, and increased tissue susceptibility to oxidative damage. However, enzymatic and nonenzymatic antioxidants have demonstrated great adaptation to acute and chronic exercise. The delicate balance between pro-oxidants and antioxidants suggests that supplementation of antioxidants may be desirable for physically active individuals under certain physiological conditions by providing a larger protective margin. <s> BIB001 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> 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, beta-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 immune system has a role is of importance. Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition. <s> BIB002 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Overtraining syndrome (OTS) is a condition wherein an athlete is training excessively, yet performance deteriorates. This is usually accompanied by mood/behavior changes and a variety of biochemical and physiological alterations. Presently, there is no global hypothesis to account for OTS. The present paper will attempt to provide a unifying paradigm that will integrate previous research under the rubric of the cytokine hypothesis of overtraining. It is argued that high volume/intensity training, with insufficient rest, will produce muscle and/or skeletal and/or joint trauma. Circulating monocytes are then activated by injury-related cytokines, and in turn produce large quantities of proinflammatory IL-1beta, and/or IL-6, and/or TNF-alpha, producing systemic inflammation. Elevated circulating cytokines then co-ordinate the whole-body response by: a) communicating with the CNS and inducing a set of behaviors referred to as "sickness" behavior, which involves mood and behavior changes that support resolution of systemic inflammation: b) adjusting liver function, to support the up-regulation of gluconeogenesis, as well as de novo synthesis of acute phase proteins, and a concomitant hypercatabolic state; and c) impacting on immune function. Theoretically, OTS is viewed as the third stage of Selye's general adaptation syndrome, with the focus being on recovery/survival, and not adaptation, and is deemed to be "protective," occurring in response to excessive physical/physiological stress. Recommendations are made for potential markers of OTS, based on a systemic inflammatory condition. <s> BIB003 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> The influence of carbohydrate (1 l/h of a 6% carbohydrate beverage), gender, and age on pro- and anti-inflammatory plasma cytokine and hormone changes was studied in 98 runners for 1.5 h after two competitive marathon races. The marathoner runners were randomly assigned to carbohydrate (C, n = 48) and placebo (P, n = 50) groups, with beverages administered during the races in a double-blind fashion using color codes. Plasma glucose was higher and cortisol was lower in the C than in the P group after the race ( P < 0.001). For all subjects combined, plasma levels of interleukin (IL)-10, IL-1 receptor antagonist (IL-1ra), IL-6, and IL-8 rose significantly immediately after the race and remained above prerace levels 1.5 h later. The pattern of change in all cytokines did not differ significantly between the 12 women and 86 men in the study and the 23 subjects ≥50 yr of age and the 75 subjects <50 yr of age. The pattern of change in IL-10, IL-1ra, and IL-8, but not IL-6, differed significantly between the C and the P group, with higher postrace values measured for IL-10 (109% higher) and IL-1ra (212%) in the P group and for IL-8 (42%) in the C group. In conclusion, plasma levels of IL-10, IL-1ra, IL-6, and IL-8 rose strongly in runners after a competitive marathon, and this was not influenced by age or gender. Carbohydrate ingestion, however, had a major effect in attenuating increases in cortisol and two anti-inflammatory cytokines, IL-10 and IL-1ra. <s> BIB004 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Apoptosis or programmed cell death is a process of fundamental importance for regulation of the immune response. Several reasons suggest that apoptosis is involved in exercise-induced alterations of the immune system such as postexercise lymphocytopenia. Healthy volunteers performed two treadmill exercise tests; the first was performed at 80% maximal oxygen uptake until exhaustion (exhaustive exercise) and the second 2 wk later at 60% maximal oxygen uptake with the identical running time (moderate exercise). Blood samples were taken before, immediately after, and 1 h after the test. Lymphocytes were analyzed for apoptotic and necrotic cells by using FITC-labeled annexin V-antibodies and nuclear propidium iodide uptake, respectively. In addition, apoptotic/necrotic cells were measured after a 24-h incubation of lymphocytes in the presence of camptothecin or phytohemagglutinin. Finally, plasma membrane expression of CD95-receptor and CD95-receptor ligand was investigated. Immediately after the exhaustive exercise, the percentage of apoptotic cells increased significantly, whereas it remained unchanged after the moderate exercise. Similar results were obtained after 24-h incubation of lymphocytes in medium alone or in the presence of camptothecin, but not with phytohemagglutinin. We found an upregulation of CD95-receptor expression after both exercise tests. However, only after exhaustive exercise a characteristic shift in CD95 expression profile toward cells with a high receptor density was observed. Expression of the CD95-receptor ligand remained unchanged after both exhaustive and moderate exercise. These results suggest that apoptosis may contribute to the regulation of the immune response after exhaustive exercise. Whether this mechanism can be regarded either as beneficial, i.e., deletion of autoreactive cells, or harmful, i.e., suppression of the immune response, awaits further investigations. <s> BIB005 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Exercise improves mood, insulin sensitivity, and plasma lipoprotein profiles and reduces blood pressure.1 Regular exercise decreases the risk of cardiovascular disease.2 Studies have associated low amounts of exercise at moderate or high intensity (which is equivalent to walking or jogging 12 mi/wk, respectively) with beneficial changes in the plasma lipoprotein profile.3 A graded response of the plasma lipoprotein levels to increasing amounts of exercise was reported, suggesting that improvements are related to the amount of exercise but not necessarily to the intensity of exercise. An increasing physical activity score shows a strong, graded, inverse association with the risk of coronary and total cardiovascular events, suggesting that exercise prevents cardiovascular mortality.4 Exercise increases insulin sensitivity and decreases and/or prevents the development or progression of type 2 diabetes mellitus in adults.5,6 Although these studies have documented the beneficial actions of exercise, the underlying mechanisms by which exercise exerts its beneficial actions are poorly understood. I suggest that exercise is anti-inflammatory in nature and thus brings about its benefits. <s> BIB006 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-α, which is reflected by elevated levels of soluble TNF-α receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-α rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-α. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-α and thereby offers protection against TNF-α-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases. <s> BIB007 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> It has been recognized for some time that cardiovascular disease and type 2 diabetes are, to a major extent, inflammatory disorders associated with an environment characterized by a sedentary lifestyle together with abundant intakes of calories. Systemic low-level inflammation is suggested to be a cause as well as consequence of pathological processes with local tumor necrosis factor alpha production as an important biological driver. It is hypothesized that physical inactivity contributes to an enhanced proinflammatory burden independently of obesity, as regular muscle contractions mediate signals with myokines/cytokines as important messengers, which suppress proinflammatory activity at distant sites as well as within skeletal muscle. Muscle-derived interleukin (IL)-6 is considered to possess a central role in anti-inflammatory activities and health beneficial effects in relation to physical exercise. It is discussed how this fits the consistent observation that enhanced plasma levels of IL-6 represent a strong risk marker in chronic disorders associated with systemic low-level inflammation and all-cause mortality. <s> BIB008 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> Skeletal muscle is comprised of heterogeneous muscle fibers that differ in their physiological and metabolic parameters. It is this diversity that enables different muscle groups to provide a variety of functional properties. In response to environmental demands, skeletal muscle remodels by activating signaling pathways to reprogram gene expression to sustain muscle performance. Studies have been performed using exercise, electrical stimulation, transgenic animal models, disease states, and microgravity to show genetic alterations and transitions of muscle fibers in response to functional demands. Various components of calcium-dependent signaling pathways and multiple transcription factors, coactivators and corepressors have been shown to be involved in skeletal muscle remodeling. Understanding the mechanisms involved in modulating skeletal muscle phenotypes can potentiate the development of new therapeutic measures to ameliorate muscular diseases. <s> BIB009 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy mARKeRs AfTeR ACUTe exeRCIse PROTOCOls AND IN ChRONIC ADAPTATION TO sysTemATIzeD PhysICAl exeRCIse <s> This study evaluated the influence of adrenergic factors on the cortisol response to maximal exercise in endurance-trained men. This was achieved by testing healthy young men during exercise while varying both the condition of β-adrenergic blockage and the presence of a well-controlled simulated competitive environment to simulate activity of the sympatho-adrenal systems. Subjects (n = 10) performed maximal exercise (running) to exhaustion on a treadmill during four conditions: (1) placebo non-competitive [PNon] (2) after administration of 80 mg propranolol non-competitive [βNon] (3) in a simulated competition after a placebo intake [PCom], and (4) in a simulated competition after propranolol intake [βCom]. Blood samples were obtained before (pre-) and 3 min after (post-) exercise and assayed for cortisol (C). The data were analyzed with a multi-factorial repeated measures ANCOVA procedure. Statistical analysis revealed a significant three-way interaction for the drug versus competition versus sampling time effects (P 0.05). The findings suggest β-adrenergic blockage and competitive conditions enhance the exercise cortisol response. In combination, however, these conditions do not act in an additive fashion. This suggests that perhaps there may be two separate influences or mechanisms (i.e., excitatory, inhibitory) on the adrenergic control of adrenocortical function, or a sympathetic compensation for β-blockage during exhaustive maximal exercise. Furthermore, the data suggests a possible “ceiling” on the hypothalamic-pituitary-adrenal axis response to exercise in endurance-trained men. <s> BIB010
Many authors have used inflammatory markers such as cytokines, leukocytes, cell adhesion molecules, cortisol, serum CK and acute phase proteins in the context of acute response and chronic adaptation to exercise. In general, the responses depend on factors such as: protocols used, intensity, frequency and volume of exercise, moments of data collection after exercise, number and fitness level of the sample subjects, markers investigated, tissues investigated and the type of sample used (animals or humans). Studies that measured the acute effects of physical exercise on inflammatory markers commonly used blood collected before and immediately after exercise, and an average number of 25 patients considered physically active, submitted to exhaustive endurance protocols (half marathon, marathon, ultramarathon, treadmill test and stationary cycle ergometer). Overall, experimental data have shown that acute exercise is associated with transient leukocytosis (especially due to neutrophilia, monocytosis and lymphocytosis), followed by partial suppression of cellular immunity by the reduced number and / or function of lymphocytes and Natural Killer cells  ; it is still possible to find a reduction in the activity of neutrophils and monocytes and decreased secretion of antibodies such as salivary IgA BIB002 . There has been found significant increases in serum concentrations of CK, CRP, cell adhesion molecules and in cortisol secretion, and increases in muscle gene expression  and in the concentration of pro and anti-inflammatory cytokines (TNF-a, IL-1β, IL-6, IL-10, IL-1ra, IL-8, IL-15) have also been observed in skeletal muscle tissue and blood BIB004 BIB010 BIB005 . Studies that measured the chronic effects of physical exercise on inflammatory markers are less common. Most of these studies used blood collected before and after the proposed protocols as a means of analysis, an average number of 34 subjects considered physically active, submitted to exhaustive endurance protocols (running, cycling and swimming). The results indicate, as a chronic effect, a reduction in the local and systemic pro-inflammatory condition. Some studies have shown attenuation in the production and secretion of acute phase proteins, especially CRP  , increased production and secretion of cytokines with anti-inflammatory function (especially IL-6 in skeletal muscle tissue and blood) BIB007 and improvement in the antioxidant power of cells BIB007 BIB001 . However, the production of IL-1β and TNF-a remained unchanged and transient or, in many times, it is not even identified, being dependent on the exercise type, intensity and duration BIB007 . Adipose tissue has also been investigated in chronic protocols and has shown the same antiinflammatory pattern  . It is important to highlight that clear experimental evidence, showing adjustments related to the control of inflammatory condition by regular and systematic physical training is still incipient, although there are good review articles suggesting that this practice can lead to an anti-inflammatory protective environment BIB006 BIB008 . That is, an increase in the pro-inflammatory organic condition by stimulus of acute exercise would be offset by the chronic anti-inflammatory environment, which would control the inflammatory magnitude and duration and would provide tissue regeneration and adaptation to the exercise loads BIB003 BIB009 . On the other hand, the literature also suggests that the beneficial effects of physical training on the inflammatory modulation is dependent on the quality and quantity of stimuli, which are directly related to the rest time among stimuli, trying to avoid the appearance of the overtraining condition. Overtraining (OT) is characterized by a continuous process of intensified physical training without adequate recovery, which may induce changes in the activation and regulation pattern of the inflammatory process BIB003 . According to the European College of Sport Science, in 2006, OT can culminate in two different states in relation to performance: short-term overreaching (functional overreaching -FOR) and extreme overreaching (non-functional overreaching -NFOR)  . The FOR state is characterized by a rapid drop in performance followed by an eventual improvement, in a process that resembles the super compensation theory  . In the NFOR state, the drop in performance has more prolonged recovery. In general, it is followed by fatigue and biochemical, immunological and physiological alterations, and even by behavioral disorders  . The NFOR state can lead to overtraining syndrome (OTS), which as the name implies, has features even more diffuse, negatively affecting various systems, presenting a very slow recovery feature  . There is a hypothesis that an increased chronic secretion of pro-inflammatory cytokines and prooxidant agents could lead to the NFOR state BIB003 BIB009 . According to this hypothesis, what triggers this state in athletes undergoing intense training and insufficient recovery time would be a progression of the adaptive stage of trauma induced in the skeletal muscles and joints to a non-adaptive stage of sub clinical injury BIB003 BIB009 . This would activate the circulating leukocytes and various tissues including skeletal muscle tissue to produce more pro-inflammatory cytokines and pro-oxidant agents BIB003 BIB009 . However, this hypothesis has not yet been experimentally verified. To investigate the relationship between physical training, overtraining, adaptation or nonadaptation conditions, and several biomarkers, including the inflammatory process, our research group has recently developed a model to induce OT in animals, which allowed the separation of animals into FOR and NFOR groups  . In the OT induction model, the animals were submitted to 11 weeks of treadmill training at a frequency of 1x/day from week 1 to week 8, 2x/day, with 4 hours rest between sessions, in week 9; 3x/day with 3 hours rest between them in week 10, and 4x/dia, with 2 hours rest between them in week 11. The data obtained from the group of animals in the FOR state showed an antioxidant and anti-inflammatory pattern, followed by increased performance at the end of 11 weeks of training.