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).