The effect of exercise on airway inflammation
Apart from investigations at the systemic level, potential influence of exercise on inflammation in upper and lower airways has been studied using non- or semi-invasive airway samplings such as nasal lavage fluid (NLF) and exhaled breath condensate (EBC) . Data acquired so far are, however, inconclusive, partly due to considerable differences in sampling methodology.
TNF-α, a pleiotropic pro-inflammatory cytokine released by a wide spectrum of cells, can be increased at both mRNA and protein level in the asthmatic airways. Mast cell-derived TNF-α has been postulated as playing a role in the pathophysiology of airway smooth muscle contraction (as reviewed in (32) and (33)). A bout of exercise induces a serum TNF-α increase followed shortly by a secondary release of interleukin 10 (IL-10) and IL-1ra. In a small study of swimmers and speed skaters (n=15) no considerable influence of acute bout of exercise on the levels of inflammatory mediators in exhaled breath condensate (EBC) was observed (29), a similar cytokine pattern disbalance was seen in lower airways of elite athletes and asthmatics. Namely, baseline TNF-α levels in EBC in non-asthmatic athletes were comparable to those observed in non-exercising asthmatics. Moreover, this was accompanied by decreased levels of anti-inflammatory IL-1ra in EBC of both athletes and asthmatics. Increased intensity of inflammation in the airways, particularly neutrophilic as reflected by increased cell counts and sputum MPO, was also described in subjects exposed to unfavorable ambient conditions on high altitudes(30). In another study, baseline sputum mRNA expression of multiple pro-inflammatory proteins was not increased in athletes, but swimming training session induced considerable increase in IL-1β, IL-6 and TNF-α mRNA expression (31). Neutrophilic airway inflammation has been consistently described in different studies performed in winter athletes (34). Inflammatory changes in athletes’ airways are reflected in considerable frequency of non-specific bronchial hyperresponsiveness observed in more than 40% of athletes, in particular those performing inter outdoor sports (20,34–36).
During interpretation of data reflecting local exercise-associated airway inflammation, several coexisting factors should be considered. Inflammatory changes in the airways may result independently from separate influence of exercise and environmental conditions. Influence of atopy per se on local airway inflammation cannot be neglected, either. The extent of contribution of each factor to airway inflammation can be determined with high degree of accuracy only if studies are specifically designed in order to include this influence.
Influence of exercise on cellular immune response mechanisms
Exercise activates various physiological mechanisms leading to alterations in number and functions of innate immunity cells. These mechanisms include: oxidative stress, increased metabolic rate, increased release of heat shock proteins, catecholamines, cortisol and insulin-like growth factor (2). Short lasting bout of exercise induces rapid and considerable yet transient increase in neutrophil numbers directly after exercise. After several hours a second wave of increased neutrophil number may be seen, depending on intensity and duration of exercise (37,38). The initial increase in neutrophils results from the release of marginal pool cells, while later increase is due to the exercise-associated cortisol action on bone marrow. Acute bout of exercise has ambiguous influence on neutrophils’ function. Degranulation, phagocytic properties and oxidative burst activity are increased in spontaneous conditions, but may be decreased after acute exercise (2) .
A more recent study has shown that in elite athletes oxidative stress markers decrease
after exercise (39). Although acute bout of exercise performed at high intensity (>60% of maximal oxygen uptake) may result in oxidative stress due to reactive oxygen species (ROS) being generated excessively by enhanced oxygen consumption (40)(a phenomenon known as exercise-induced oxidative stress), several studies have demonstrated that continuous aerobic training reduces ROS production and increases antioxidant defenses .
An acute bout of exercise causes transient increase in peripheral monocytes (44–49) probably due to their release from marginal pool . In addition, changes in monocytic surface proteins and cytokine expression can be observed following a single exercise bout, with the pro-inflammatory CD14+/CD16+ phenotype predominance (50,51). Acute bout of exercise has also been reported to decrease the expression of Toll-like receptors (TLR) 1, 2 and 4 (52–54) accompanied by increased LPS-induced release pro-inflammatory cytokines (51).
Regarding tissue macrophages, stimulatory effects of exercise on their phagocytosis, anti-tumor activity, reactive oxygen and nitrogen metabolism and chemotaxis were described . Tissue macrophages are characterized with diversity and plasticity. In response to various stimuli they may present pro- or anti-inflammatory phenotype referred to as M1 and M2, respectively. The M1 phenotype results from stimulation by TLR ligands and IFN-γ whereas the M2 phenotype is an effect of alternative stimulation of macrophages by IL-4/IL-13 (55). Increased switching from M1 to M2 macrophage phenotype is one of the postulated mechanisms of anti-inflammatory and somewhat bronchoprotective action of exercise (56). To date, the impact of acute exercise on macrophage polarizations has mainly been studied in animal models and M1-to-M2 macrophage phenotype switching was observed (57). Studies investigating the effects of exercise on macrophage polarization were performed in several tissues, however, they mainly assessed the influence of prolonged physical activity programs (56,58). In a small sample of Taiwanese footballers, acute aerobic exercise caused decrease of proinflammatory M1 phenotype with no effect on M2 phenotype markers (59). Considering the paucity of human studies targeting influence of acute bout of exercise on macrophage polarization and – through this - on tissue inflammation, it is highly desirable that these issues be addressed in the nearest future. We can identify this area as an unfilled gap and potentially promising research niche in the field of exercise immunology.
Studies targeting dendritic cells (DCs) in the context of acute exercise are not numerous, either. Due to their role in educating naïve T cells during differentiation, DCs can influence the intensity and nature of Th-dependent response. Studying the murine model of asthma, Mackenzie et al assessed the influence of a single bout of moderate exercise on DC maturation and activation (60). Under these conditions, DC maturation was decreased which was evidenced by altered expression of MHC-II, CD80, CD83 and CD86. In the rat model of acute exercise, Liao et al described an increase only in DC number but not functional modifications as assessed by surface molecules’ expression (61). In another study, the same group found some functional activities to be increased post-exercise in rats (e.g., MHC-II expression, cytokine production). In a study performed in healthy human adults, LaVoy et al reported that acute exercise bout may contribute to increased generation of monocyte-derived DC in 8-day culture setting, which can constitute a useful tool of acquiring DC for research and immunotherapy purposes (49). Taken together, data published to date indicate that both DC number and function can be modified by acute exercise. Considering important role of these cells in regulation of immune response (including development of type 2 inflammation), impact of exercise on DCs definitely deserves more research interest with particular stress on human studies.
Lymphocytosis induced by acute bout of exercise has been well-documented in human studies. Both T CD4+ and T CD8+ increase in number after acute strenuous exercise in an intensity proportionate manner. However, T CD4+ cells increase in larger absolute numbers due to their higher baseline count in peripheral blood, whereas higher β2-adrenergic receptor density on the surface of T CD8+ cells makes them highly responsive to exercise and leads to larger relative post-exercise increase in their number (63). Both T cell subsets react differently to variable recovery periods between single exercise bouts. T CD4+ and CD8+ lymphocytes may equally fail to return to baseline numbers should the recovery period be shortened. However, subsequent acute exercise leads to more prominent increase in T CD8+ as compared to T CD4+ cell numbers (64).
Exercise-induced shifts in Treg numbers appear to be dependent on exercise intensity and duration. Presently, no consistent data exist on the effect of acute exercise on TCD4+CD25+FoxP3+ cell numbers (63) nor is anything known on the mechanism which might underlie potential effects on Treg cells. For instance, it is postulated that the apparent decline in Tregs observed after triathlon or marathon may be due either to cell apoptosis or their redistribution into peripheral tissues. Recently, a biphasic response of Treg count to acute exercise was described (65)), which adds more to the complexity of the picture and confirms that modulation of Treg-dependent response through acute exercise remains an open field for research.
Considering the influence of chronic exercise training on T cell numbers, significant decrease has been observed in case of IFN-γ+ T cells whereas no considerable impact of exercise upon type 2 (I.e., IL-4+ T cells) was noted in elite cyclists during their training period (66). Decreased Th1 and Treg cells numbers accompanied by increased Th2 numbers were seen four weeks after marathon participation in trained runners as compared with non-running controls (67). These shifts may underlie the increased infection rate in elite athletes. Lastly, a Chinese transcriptome study showed that regular endurance exercise may contribute to transcriptional changes resulting in downregulation of genes coding for proinflammatory proteins (68).
Effects of both acute and chronic exercise on immune response cells’ numbers and functions are summarized in Tables 1 and 2 .
Exercise and humoral immune response
Decreased efficiency of humoral immune response on a mucosal level is consistently associated with physical exercise and manifests predominantly with lowered secretory IgA (sIgA) levels in saliva. Recently, the significance of other salivary antibacterial proteins in exercise-induced modifications of immune response has been discussed . Results of numerous studies have shown increased susceptibility to URTIs in the period directly following participation in a long-distance run (3,4,69,70). Moreover, an association of decreased salivary IgA with increased probability of URTIs has been observed in studies involving elite athletes (71,72)
During the periods of intensive training as a part of sports (71–74) and military (75–77) curriculum, shifts in salivary IgA are observed; decreased sIgA is accompanied by increased infection susceptibility, although the correlation is not always clear and evident (2). In addition, other interfering factors should be considered during interpretation of data regarding influence of short bout of exercise on sIgA levels and susceptibility to infections. These factors include: type and pattern of exercise, its duration as well as general subject’s fitness. An extremely intensive training regime is frequently associated with other potential modifiers of immune response, such as increased energy expenditure, sleep deprivation, altitude above sea level and psychological stressors (2,78–80) .
Moderate physical activity as a part of lifestyle modification leads to increase in salivary IgA levels. This further confirms beneficial anti-inflammatory and immunomodulatory influence of regular physical activity performed at a non-elite level (81,82).
Contradictory results have been observed regarding serum concentrations of immunoglobulins. According to several authors, serum IgG’s increase in endurance athletes shortly after acute exercise bout as well as over longer periods of repeated trainings (83–86). Other studies have shown, however, considerable falls in serum IgG associated with strenuous exercise, such as 75 km run, 3-week rugby training camp or 14-week running training program (87–90). Serum IgM studies brought similarly ambiguous results: both decreases (83,87–89) and increases (84,91) under intensive exercise conditions have been described. Few studies in which serum IgD levels – as a marker of B cell activation - were assessed have also brought conflicting results (83,84). Shifts in IgE levels under strenuous exercise conditions have not been extensively studied, either. A large inter-subject variability in exercise-associated changes in IgE were observed, which is probably due to genetically conditioned intensity of IgE synthesis and release . Regarding moderate intensity physical training, it has been suggested that it may induce a decrease in both total and allergen specific IgE levels (92).