Oxidative Medicine and Cellular Longevity

Review Article

Update on the Mechanisms of Pulmonary Inflammation and Oxidative Imbalance Induced by Exercise

Table 1

(a) Human studies on lung oxidative stress and inflammation induced by acute exercise. (b) Human studies on lung oxidative stress and inflammation induced by chronic exercise.

(a)


Author, year	Aim	Sample’s characteristics	Exercise protocols	Samples obtained	Oxidative or inflammatory main results

Adachi et al. 1997 [50]	eNO and VNO in patients with CHF during exercise	CHF patients and healthy control subjects (C)	Maximal incremental cycloergometer test in CHF patients (10 W/min) and C (25 W/min) until exhaustion	EB	DE: ↑ VNO during exercise peak in C

Agostoni and Bussotti 2003 [51]	Correlation between eNO and lung mechanics during exercise in CHF	CHF patients and healthy control subjects (C)	25-W constant workload exercise cycle-ergometry test	EB	DE: ↓ eNO during 3rd and 5th minutes of exercise in C

Araneda et al. 2005 [46]	Lung oxidative damage from exercise at a medium altitude	Highly trained mountain bikers	Three repetitions of cycle-ergometries of 1 min at maximum intensity in 670 and 2160 MASL with breaks of 1 min	EBC and serum	PE: ↑ [MDA] in EBC, with no changes in serum at 2160 MASL

Araneda et al. 2012 [52]	Duration of a long distance exercise on pulmonary oxidative damage	Amateur runners	Urban 10 km (~53 min), 21 km (~101 min), and 42.2 km races (~246 min)	EBC	PE: ↑ [H₂O₂] and ↑ [] in 21 km and 42.2 km races and no changes in [MDA]; there was a tendency to ↓ of pH

Araneda et al. 2014 [53]	Pulmonary oxidative damage in long distance exercise	Healthy active subjects	10 km race in outdoor athletic track (~50 min)	EBC	PE: ↑ [H₂O₂], ↑ with no changes in the [MDA]; there was a tendency to ↑ of pH

Bikov et al. 2010 [54]	Changes in [Cys-LTs] caused by exercise in asthmatic patients	Nonsmoking asthmatic patients (A) and nonsmoking healthy control subjects (C)	Race on treadmill at a speed and slope maintaining 80–90% (220 − age), which was regulated in 2 min and then maintained during 6 min	EBC	PE: with no changes in [Cys-LTs] in C, but ↑ in A

Bikov et al. 2014 [55]	Changes in during EIB in asthmatic patients	Asthmatics, who reported breathlessness following exercise, and healthy control subjects (C)	Exercise challenge test on a treadmill (details were not described by authors)	EBC and EB	PE: no change of pH in EBC in C

Bonsignore et al. 2001 [56]	Endurance exercise on inflammatory cells in AWs and eNO	Amateur runners	Marathon race (~179 min)	IS and EB	PE: ↑ PMN in IS and ↑ eNO in EB

Bonsignore et al. 2003 [57]	Swimming on inflammatory cells and eNO in the AWs	Swimmers (S) and healthy control subjects (C)	Swimming of 5 km only in the swimmers group, an open pool series (~70 min) and other series in the sea (~54 min)	IS and EB	B: >PMN and <MØ in the IS of S versus C PE: ↑ eosinophils, ↑ lymphocytes, and ↓ MØ in the sea versus swimming pool; eNO was > in the sea in comparison to swimming pool

Carbonnelle et al. 2008 [58]	eNO after swimming sessions	Trained healthy young people, not trained with swimming	Swimming in 2 sessions of 45 min (~1300 m), in a disinfected pool with [NaClO] and another sanitized with electrical process	EB	PE: ↑ eNO only in sanitized pool

Chimenti et al. 2009 [40]	Inflammation of the AWs in urban races in different climatic seasons	Amateur runners	21 km race in autumn (~89.1 min), 12 km race in winter (~46.1 min), and 10 km race in summer (~35.4 min)	IS	B: ↑ PMNs with ↑ [TNF-α] and ↑ [IL-8] PE: PMNs tended to ↑

Chimenti et al. 2010 [5]	Damage and inflammation of the lung epithelium in a long distance exercise	Amateur runners and healthy control subjects	20 km outdoor races (~90 min)	IS and serum	PE: ↑ [IL-8] in IS and ↑ CC16 in serum

Chirpaz-Oddou et al. 1997 [59]	eNO and VNO during exercise	Healthy control and trained subjects	Incremental cycloergometry to exhaustion with 5 min of passive recovery in sedentary subjects (♂ ~30 min and ♀ ~20 min) and trained subjects (~14 min)	EB	DE: ↓ eNO progressive with ↑ exercise intensity from 65% VO₂max and ↑ VNO with the ↑ of the intensity of exercise > 30 W in all subjects

Clini et al. 2000 [60]	To evaluate eNO during exercise in patients with stable COPD	COPD patients and healthy control subjects (C)	Maximal cycle-ergometry test (cadence: 60 cycles/min and load: 10 W/min) until exhaustion	EB	DE: ↓ eNO at peak exercise and ↑ VNO in C

De Gouw et al. 2001 [61]	Role of eNO in the airway response to exercise by using L-NMMA, L-arginine, or placebo as pretreatment to exercise challenge	Asthmatic patients and healthy control subjects (C)	Cycle-ergometry for 6 min using dry air, while ventilation was kept constant in 40–50% of his or her predicted maximal voluntary ventilation (35 × FEV₁)	EB	PE: ↑ eNO 30 min after exercise in C

Denguezli-Bouzgarrou et al. 2006 [62]	Endurance exercise and inflammatory cells of the AWs	Long-distance runners	Races on treadmill at 80% of MAS (~60 min)	IS	PE: ↑ PMNs, ↓ MØ, and ↑ lymphocytes

Denguezli-Bouzgarrou et al. 2007 [63]	Inflammatory mediators, cellular composition in AWs, and acute exercise during a sports season	Long-distance runners	Race at 80% MAS during the basic, precompetitive, and competitive period of a sport season in 1 year (~60 min)	IS	PE: ↑ PMNs in the precompetitive and competitive period. ↑ MØ in the precompetitive period; also, ↑ [histamine], ↑ [IL-8], ↑ [LTB₄], and ↑ [LTE₄] in the competitive phase

Evjenth et al. 2013 [64]	To investigate the effect on of a standardized exercise challenge test on a treadmill	Nonasthmatic children with and without allergic rhinoconjunctivitis (AR) symptoms	Run on treadmill (6 to 8 min); heart rate target during the last 4 min was 95% of predicted maximum heart rate (220 − age)	EB	PE: ↓ eNO in nonasthmatic children without allergic rhinoconjunctivitis

Font-Ribera et al. 2010 [65]	Inflammation and postexercise pulmonary oxidative stress	Healthy subjects	Swimming in a chlorinated indoor-swimming pool (40 min), whose average speed was 22.5 ± 9.7 m/min	EBC and EB	PE: no changes of eNO in EB; [RANTES], [IL-12p70], [IFN-γ], [IL-4], [IL-8], [IL-10], [IFN-γ-induced protein 10], [TNF], [VEGF], and [8-isoprostane] in the EBC were not modified

García-Río et al. 2006 [66]	before and after exercise challenge in patients with asthma and its relationship with airway obstruction	Nonsmoking, steroid-naïve, atopic patients with mild persistent asthma and nonsmoking, nonatopic, healthy subjects (C)	Performing an exercise challenge on a cycloergometer, with monitored ventilation (exercise parameters were not presented)	EB	PE: with no changes in eNO of healthy subjects

Hopkins et al. 1997 [67]	Pulmonary capillary pressure and function of the alveolar-capillary barrier during intense exercise	Athletes with signs of hemoptysis by exercise and healthy control subjects	4 km cycling with 12% hill sloping during ~7 min	BALF	PE: >alveolar MØ, >[LTB₄], and < lymphocytes in athletes versus control subjects

Kippelen et al. 2002 [68]	eNO level in endurance-trained athletes during and after intense exercise	Nine athletes with exercise-induced hypoxaemia (EIH), 12 athletes without EIH, and 10 untrained subjects	15 min intense cycling exercise at 90% VO₂max	EB	DE: ↓ eNO and ↑ VNO (last 3 minutes) in all groups

Larsson et al. 1998 [32]	Cold air and inflammation in the AWs during rest and exercise	Healthy subjects	Race on treadmill at −23°C and +22°C, each with 4 stages with 15 min at moderate intensity and 15 min of recovery	BALF	PE: at −23°C ↑ granulocytes and ↑ MØ; no changes in [IL-8]

Lovell et al. 2000 [69]	eNO and incremental exercise test in chronic congestive cardiac failure	Chronic congestive cardiac failure patients and healthy control subjects (C)	Performing Bruce protocol modified by inclusion of an initial 3 min stage at 5% incline, later performing a constant workload test (6 min at 2.7 km h⁻¹ and 5% incline)	EB	DE: ↓ eNO and ↑ VNO during Bruce test in C; ↑ VNO during constant workload test

Mantione et al. 2007 [70]	eNO breath levels just before engaging in their respective activity	Healthy control subjects	Going up and down the stairs on a 20-foot staircase for 2 min	EB	PE: ↓ eNO 1 minute after exercise

Matsumoto et al. 1994 [71]	eNO and VNO during exercise	Healthy subjects	Cycle-ergometry at 100 W and maximum intensity with 5 min of recovery (~13 min)	EB	DE: ↑ VNO at 100 W and at maximum pedaling intensity

Marek et al. 2008 [72]	[L-lactate] and [H₂O₂] during exercise	Healthy subjects	Cycle-ergometer steady-state exercise at 60 W (~7 min) and 120 W (~5 min)	EBC	DE: ↑ [L-lactate] and ↑ [H₂O₂] in 60 W and 120 W

Marek et al. 2009 [73]	Maximal exercise, H₂O₂ release rate, and acid-base status	Amateur athletes	Incremental cycloergometry to exhaustion (~13 min)	EBC	PE: ↑ [H₂O₂] with no changes in pH nor []

Marek et al. 2013 [74]	Exercising in cold weather and release of	Healthy subjects	Races on treadmill at 75–80% at ~18°C and ~−15°C (~50 min)	EBC	PE: ↑ [H₂O₂] and ↑ rate of H₂O₂ release in both temperatures

Maroun et al. 1995 [75]	Physical condition and release of eNO during exercise	Healthy sedentary subjects (S), active subjects (Ac), and athletes (A)	Cycle-ergometries in steady-state at 1 and 2 L/min of VO₂ only performing an additional one at 4 L/min of VO₂	EB	PE: ↓ eNO at >VO₂ in S and Ac; ↑ lineal of VNO with ↑ VO₂ in A

Mercken et al. 2005 [76]	Exercise-induced oxidative stress in COPD	COPD patients and healthy control subjects (C)	Incremental cycle-ergometry exercise test until exhaustion and submaximal constant work rate exercise test (60% maximal power output)	EBC	PE: ↑ [H₂O₂] in maximal but not in submaximal exercise in C

Mercken et al. 2009 [77]	Pulmonary oxidative stress by endurance exercise in COPD and healthy subjects	COPD patients and healthy control subjects	Cycle-ergometry on one leg at 40% of maximum power output (20 min)	EBC	PE: ↑ [H₂O₂] in COPD patients but not in healthy control subjects

Morici et al. 2004 [78]	VE during exercise and inflammation in the AWs	Young rowers	Maximal run of 1000 m on the rower ergometer (~3 min)	IS	DE: ↑ tendency in epithelial cells at a higher VE PE: ↑ MØ with both ↑ VE/kg and ↑ VT/kg

Nowak et al. 2001 [79]	Prooxidants and oxidative damage by moderate exercise	Healthy subjects	Cycle-ergometer exercise test at 120 W during 6 min or until a HR of 120 bpm is reached	EBC	PE: with no changes in [H₂O₂] and [TBARs]

Nadziakiewicz et al. 2006 [80]	Effects of the physical activity on eNO levels in healthy subjects and in CAD patients	CAD patients and healthy control subjects smokers and nonsmokers	Bruce protocol exercise test	EB	PE: without changes in eNO in healthy control subjects nonsmokers

Pedersen et al. 2009 [81]	Inflammation in the AWs after 1-exercise session	High performance swimmers	Swimming in indoor-swimming pool at moderate intensity (45 min) whose average heart rate was 162 bpm	EBC and IS, EB	PE: no changes in the cellular composition in IS, eNO in EB, nor pH in EBC of swimmers

Pogliaghi et al. 1997 [82]	VNO after modifying pulmonary blood flow with head-out water immersion or increased gravity at rest and during exercise	Nonsmokers and healthy subjects who underwent air with normal conditions, water immersion, or increased gravity (1 Gz or 2 Gz)	Incremental cycle-ergometry test, loading was increased progressively by 50 W every 3 min until voluntary exhaustion	EB	DE: ↓ eNO and ↑ VNO in all groups

Pucsok et al. 2007 [83]	Lung PGE₂ and TXB₂ and exercise	Judo competitors	Incremental run on treadmill until VO₂max is reached (run time was not recorded)	EBC	PE: ↑ [PGE₂] and ↑ [TXB₂] in ♂, but not in ♀

Riediker and Danuser 2007 [84]	Low-intensity physical activity and pH	Healthy subjects	Walk on treadmill at 60% predicted with 1 min pause every 10 min (~30 min)	EBC	PE: ↑ pH

Riley et al. 1997 [85]	NO production in patients with abnormalities of the pulmonary circulation	PPH (primary pulmonary hypertension), PF (pulmonary fibrosis), and normal subjects group	Maximal (20 W/min in the normal subjects and 15 W/min in the PF patients and individual estimated exercise tolerance in PPH patients) and submaximal constant work rate cycle-ergometry exercise test (work rate VO₂ midway between each patient's anaerobic threshold and VO₂max)	EB	DE: ↓ eNO and ↑ VNO in normal subjects at peak exercise in maximal and constant work rate exercise test

Rolla et al. 2003 [86]	Relationship between eNO and exercise tolerance in patients with moderate MS	Patients with moderate MS and healthy control subjects (C)	Symptom-limited incremental exercise test with an upright cycle-ergometer (25 W every 3 min until exhaustion)	EB	DE: ↓ eNO and ↑ VNO in all groups at the end of exercise

Shin et al. 2003 [87]	Relationship between exercise and NO exchange	Nonsmoking healthy adults	High-intensity exercise treadmill test at 90% of the predicted maximum heart rate (220 − age in years) for 20 min	EB	PE: ↑ VNO

St Croix et al. 1999 [88]	Effect of exercise on endogenous NO formation by measuring eNO at a constant airflow rate	Healthy, nonasthmatic, and nonsmoking subjects	3 min of constant-load cycle-ergometry exercise test at three different exercise intensities corresponding to 30%, 60%, and 90% VO₂max	EB	PE: ↓ eNO and ↑ VNO for all intensities of exercise in healthy subjects

Therminarias et al. 1998 [89]	Exercise in cold air on eNO and VNO	Highly trained subjects (cross-country skiers, triathlon, and running)	Incremental cycloergometry to exhaustion in a climate chamber at +22°C and −10°C (~30 min)	EB	DE: ↓ eNO with the ↑ of the intensity >60 W in +22°C and ↑ VNO with the ↑ of the intensity >30 W in both temperatures

Trolin et al. 1994 [90]	eNO and VNO during exercise	Healthy subjects	Moderately heavy exercise on a cycloergometer (♀: 90 W for women and ♂: 150 W for ♂)	EB	DE: ↓ eNO

Tufvesson et al. 2013 [91]	Relationship between CC16 levels in plasma and urine after exercise with exhaled breath temperature and eNO	Asthmatic and healthy control subjects	During first six minutes speed and slope were adjusted to maintain the heart rate subject to 90% of their theoretical maximum heart rate (220 − age); the next two minutes were adjusted again to reach maximum effort	EB	PE: ↓ eNO in both groups

Verges et al. 2006 [92]	Effect of prolonged exercise on the NO concentration in the lung	Nonsmokers undertaking a moderate to intense training program participated in the study	100 min exercise test was performed on a cycle-ergometer (5 min of rest, 30 min warm-up at 25% , 10 min at 60% , 2 min at 25% repeated five times (S1 to S5), and 10 min of active recovery at 25% )	EB	DE: ↓ eNO for all exercise sessions (WU, S1 to S5, and active recovery)

Wetter et al. 2002 [93]	EIAH and pulmonary inflammation	Endurance athletes with EIAH who used anti-inflammatory or placebo	Maximal incremental run on treadmill to exhaustion (~18 min)	IS	PE: with no PMNs, lymphocytes, nor MØ; ↑ [Histamine] in placebo

Yasuda et al. 1997 [94]	To examine the origin and role of eNO during exercise	Healthy control subjects	Two sets of 10 minutes in a cycle-ergometer (5 min without load and 5 minutes with 60 W and 60 RPM) separated, with 15 minutes between them	EB	DE: with no changes in eNO

Zietkowski et al. 2010 [95]	To assess the possible association of EIB with low-grade systemic inflammation in asthmatic patients	Asthmatics (14 with EIB, 10 without EIB) and healthy volunteers	Cycle-ergometer test for 9 min with a fixed workload adjusted to increase the heart rate to 85% of the maximum predicted for the age of each patient	EBC	PE: with no changes in hs-PCR in healthy volunteers

AWs: airways; BALF: bronchoalveolar lavage fluid; CAD: coronary artery disease; CC16: Clara cell secretory protein; CHF: chronic heart failure; COPD: chronic obstructive pulmonary disease; Cys-Lts: cysteinyl leukotrienes; EB: exhaled breath; EBC: exhaled breath condensate; EIAH: exercise-induced arterial hypoxemia; EIB: exercise-induced bronchoconstriction; eNO: exhaled nitric oxide; : fractional exhaled nitric oxide; : bicarbonate; H₂O₂: hydrogen peroxide; HRmax: maximum heart rate; IFN-γ: interferon gamma; IFN-γ-induced protein-10: interferon-gamma-induced protein-10; IL-12p70, IL-4, IL-8, and IL-10: interleukin-12p70, interleukin-4, interleukin-8, and interleukin-10; IS: induced sputum; L-NMMA: N-monomethyl-L-arginine; L-lactate: lactate; LTB₄: leukotriene B₄; LTE₄: leukotriene E₄; MØ: macrophages; MAS: maximal aerobic speed; MS: mitral stenosis; MDA: malondialdehyde; MPO: myeloperoxidase; MASL: meters above sea level; NaCLO: sodium hypochlorite; : nitrite; NO output: nitric oxide output (eNO × VE); PGE₂: prostaglandin E₂; : maximal power output; RANTES: regulated upon activation, normal T-cell expressed, and secreted; TBARs: thiobarbituric acid reactive species; TNF(-α): tumor necrosis factor (alpha); TXB₂: thromboxane B2; Se: selenium; VE: minute ventilation; VEGF: vascular endothelial growth factor; VNO: volume of nitric oxide; VO₂max: oxygen uptake (maximal); VT: tidal volume. In “Oxidative or inflammatory main results,” DE: during exercise and PE: postexercise. In “Aim,” the effect of exercise was not the primary aim of the study.

(b)


Author, year	Aim	Sample’s characteristics	Experimental protocols	Samples obtained	Oxidative or inflammatory main results

Belda et al. 2008 [96]	Type of sport (aquatic or terrestrial) and cell count	Elite healthy athletes and with asthma	Comparison of baseline samples between healthy and asthmatic athletes who practice water sports in pools or terrestrially (T: ~20 h/wk, with the exception of healthy subjects in water with T: ~10 h/wk)	IS	There was a positive correlation between PMNs with training time and water sport in the pool

Carraro et al. 2006 [97]	eNO in regular attendance to swimming pools	Children swimmers attending and control children not attending the swimming pool	Comparison of baseline samples between swimmers who attended a swimming pool (1 h/week/6 months) and control subjects	EB	There were no differences in eNO between both groups

Ferdinands et al. 2008 [98]	Exercise in contaminated environment and inflammation	Cross-country athletes and healthy control subjects	Comparison of baseline samples before and after 10 workouts in 15 d (~1 h/d)	EB	<pH in cross-country athletes compared to their control subjects between their respective sample times

Heinicke et al. 2009 [47]	Pulmonary oxidative damage and prolonged stay in medium height training	Biathletes and sedentary control subjects	Comparison of baseline samples between biathlete (T: ~5 h/wk) and control subjects; both groups were exposed to 2800 MASL during the 6 weeks	EBC	[H₂O₂] and [8-isoprostane PGF₂α] with no differences between groups; by gathering data ↑ [H₂O₂] and tendency to ↑ [8-isoprostane PGF₂α]

Helenius et al. 1998 [99]	AWs inflammation in swimmers	Elite swimmers and nonathletic control subjects	Comparison of baseline samples between swimmers (T: 800–3380 km/year) and control subjects	IS	>Eosinophils, >PMNs, >[EPO], and >[human neutrophil lipocalin] in swimmers in comparison to control subjects

Helenius et al. 2002 [100]	Retirement from swimming in relation to AWs inflammation	High performance swimmers	Comparison of baseline samples between active (T: ~1870 km/year) and inactive swimmers (3 months of inactivity)	IS	>eosinophils and >lymphocytes in active swimmers than inactive swimmers

Karjalainen et al. 2000 [101]	Inflammatory cells in skiers, mild asthmatics, and healthy control subjects	Elite healthy skiers and nonathletic control subjects	Comparison of baseline samples between skiers (T: 200–630 h/year) and control subjects	Endobronchial biopsy	>lymphocytes-T (43 times), >MØ (26 times), >eosinophils (2 times), and >PMNs (2 times) in skiers in comparison to control subjects

Martin et al. 2012 [102]	AWs inflammation and exposure to swimming pool in athletes	Endurance athletes	Comparison of baseline samples of pool based (5 h/wk) and non-pool-based (0.5 h/wk) athletes (T: ~15 h/wk)	EB and IS	PMNs and eosinophils in IS and eNO in EB were not different between groups

Sue-Chu et al. 1999 [103]	AWs inflammation in skiers	Cross-country skiers and nonathletic control subjects	Comparison of baseline samples during the competitive period, in autumn and winter, between skiers (T: 435 h/year) and control subjects	BALF	>total cells, >lymphocytes, and >mast cells in skiers in comparison to control subjects, with no differences in [TNF-α] and [MPO]

Sue-Chu et al. 2000 [104]	Budesonide and AWs inflammation in skiers	Elite cross-country skiers with asthmatic symptoms and budesonide or placebo supplementation	Comparison of baseline samples among skiers, after 20 weeks of supplementation with 800 µg/d budesonide (T: ~427 h/year) or placebo (T: ~468 h/year)	BALF and endobronchial biopsy	Lymphocytes, MØ, eosinophils, PMNs, and mast cells were not different between groups

AWs: airways; BALF: bronchoalveolar lavage fluid; EB: exhaled breath; EBC: exhaled breath condensate; EPO: eosinophil peroxidase; H₂O₂: hydrogen peroxide; IS: induced sputum; 8-isoprostane PGF2α: 8-isoprostane prostaglandin F₂ alpha; MØ: macrophages; MPO: myeloperoxidase; NO: nitric oxide; PMNs: polymorphonuclear neutrophils; T: training volume; TNF-α: tumor necrosis factor-alpha. In “Aim,” the effect of exercise was not the primary aim of the study.