Exercise Training Induces a Shift in Extracellular Redox Status with Alterations in the Pulmonary and Systemic Redox Landscape in Asthma

Abstract

Redox dysregulation and oxidative stress have been implicated in asthma pathogenesis. Exercise interventions improve symptoms and reduce inflammation in asthma patients, but the underlying mechanisms remain unclear. We hypothesized that a personalised exercise intervention would improve asthma control by reducing lung inflammation through modulation of local and systemic reactive species interactions, thereby increasing antioxidant capacity. We combined deep redox metabolomic profiling with clinical assessment in an exploratory cohort of six female patients with symptomatic asthma and studied their responses to a metabolically targeted exercise intervention over 12 weeks. Plasma antioxidant capacity and circulating nitrite levels increased following the intervention (p = 0.028) and lowered the ratio of reduced to oxidised glutathione (p = 0.029); this was accompanied by improvements in physical fitness (p = 0.046), symptoms scores (p = 0.020), quality of life (p = 0.046), lung function (p = 0.028), airway hyperreactivity (p = 0.043), and eosinophilic inflammation (p = 0.007). Increased physical fitness correlated with improved plasma antioxidant capacity (p = 0.019), peak oxygen uptake and nitrite changes (p = 0.005), the latter also associated with reductions in peripheral blood eosinophil counts (p = 0.038). Thus, increases in "redox resilience" may underpin the clinical benefits of exercise in asthma. An improved understanding of exercise-induced alterations in redox regulation offers opportunities for greater treatment personalisation and identification of new treatment targets.

Keywords: asthma; exercise; inflammation; oxidative stress; reactive species interactome.

Conflict of interest statement

T.M.A.W reports grants and personal fees from AstraZeneca, personal fees and other from my mhealth, grants and personal fees from GlaxoSmithKline, grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, grants, and personal fees from Synairgen, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1

Changes in pattern of responses of the free thiol metabolome (A–J). Data presented for n = 6 before and after acute physiological challenge of a cardiopulmonary exercise test, presented as mean and SEM, with overlaid individual data (circles, squares, up- and downward triangles). Data presented in nM or concentration ratio. Green bars = baseline, orange bars = week 3, blue bars = week 6 and grey bars = week 12. Abbreviations: GSH: reduced gluthathione; GSSG: oxidised glutathione; Cys: cysteine, CySS: cystine; HCys: homocysteine, HCySS: homocystine, * = p < 0.05.

Figure 2

Pattern of response to changes in concentration of total and bound thiols in plasma (A–H). Data presented for before and after acute physiological challenge of a cardiopulmonary exercise test at each sampling point throughout the training intervention, presented as mean and SEM, with overlaid individual data (circles, squares and triangles; for the sake of direct comparison to free thiols, all concentrations are presented in [nM]). Green bars = baseline, orange bars = week 3, blue bars = week 6, and grey bars = week 12. Abbreviations: GSH: gluthathione; Cys: cysteine; HCys: homocysteine, * = p < 0.05.

Figure 3

Pattern of redox responses to pre- and post-acute exercise challenge at each sampling point in study for plasma concentrations of nitrite (A), nitrate (B), nitroso species (C), TBARS (D) and FRAP (E), presented as mean and SEM, with individual data (circles, squares and triangles) overlaid. Data presented in µM or nM. Green bars = baseline, orange bars = week 3, blue bars = week 6, grey bars = week 12. Abbreviations: CPET: cardiopulmonary exercise test; RXNO: total nitroso species; TBARS: thiobarbituric acid reactive substances; FRAP: ferric reducing ability of plasma. * = p < 0.05.

Figure 4

Significant correlations (Spearman’s rho correlation) between improvements in physical fitness, increased redox capacity and inflammation. (A) A greater increase in maximum oxygen uptake is associated with a greater increase in pre-CPET nitrite from baseline (r = 0.943, p = 0.019), (B) a greater increase in oxygen uptake at AT strongly correlates with a larger increase in FRAP (r = 0.886, p = 0.019), and (C) a greater increase in pre-CPET nitrite significantly correlates with a greater reduction in peripheral blood eosinophil levels (r = −0.837, p = 0.038). Abbreviations AT: (oxygen uptake at) anaerobic threshold; FRAP: ferric reducing ability of plasma.