Exercise as an immunomodulatory mechanism in asthma

Abstract

The prevalence of asthma remains high worldwide, and despite the development of biological treatments, many patients remain sub optimally controlled, and mortality rates have been static for decades. Exercise immunology is an expanding field, and there is growing evidence that exercise can modulate the inflammatory and immune processes in asthma. Changes in redox status have been linked with asthma severity, and modulation of redox balance via upregulation of the master antioxidant NRF2 has been proposed as the mechanism through which exercise exerts its disease modifying properties. Despite this, and national and international guidance to increase exercise, patients with asthma are less likely to engage in physical activity than non asthmatics. The aim of this thesis was to investigate the effect of an interval exercise training programme on symptom control and inflammation in patients with suboptimally controlled asthma, and the role of NRF2 driven increases in redox buffering capacity in mediating this response. A 12-week exercise intervention resulted in significant improvements in symptom and quality of life scores, in addition to improvements in asthma related inflammatory markers and lung function. In terms of mechanistic investigation, downstream markers of redox regulation increased, with demonstration of association between improvements in fitness, increases in antioxidant capacity and inflammation, through to overall improvements in lung function and asthma symptoms. Given the early exploratory data to support my hypothesis, alongside challenging recruitment and high participant drop out rate, identification of the barriers to exercise for patients with asthma was important. Therefore, I assessed perceived barriers to exercise in the WATCH Cohort of Difficult Asthma. The perceived burden of exercise therapy in patients with difficult asthma was demonstrated to be at a level comparable to those with cardiovascular disease, and higher than in patients with cancer. A high perceived burden of exercise therapy was significantly associated with increased asthma symptoms, anxiety and depression, reduced quality of life and increased number of rescue oral steroid courses whilst more biological markers of disease such as lung function, blood eosinophil count, FeNO and hospitalisations in the previous year were not. This analysis described herein suggests exercise intervention in symptomatic asthma is tolerated and beneficial for physical fitness, and symptom control, with associated improvement in inflammatory parameters and lung function. The mechanism of these improvements may be via improved redox buffering capacity, resulting in increased tolerance to disease related stressors. Demonstration that perceived barriers to exercise are associated with higher symptom scores and psychological burden, but not biological markers of disease severity, suggest that an exercise intervention along with psychological input may help facilitate increased uptake of a disease modifying lifestyle change. Further work is required to validate these exploratory results in a fully powered study, which will require adaptation to accommodate COVID safe protocols.

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ORCID for Karl Staples: orcid.org/0000-0003-3844-6457

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