Effect of High-intensity Interval Training on the Lung in Patients With COPD Referred for Lung Volume Reduction Surgery: The PREGENERATE Trial

Patients with chronic obstructive pulmonary disease (COPD) suffer from a progressive loss of lung function that leads to low physical performance, poor quality of life, and early death. Pulmonary rehabilitation, including exercise training, is considered the most effective non-pharmacological intervention for improving quality of life in patients with COPD. However, its use is halted by the lack of understanding of the mechanism of exercise-induced improvement in COPD, and is widely thought not to have any effect on lung function, at least as measured by dynamic spirometry and diffusion capacity measured at rest in the upright position. It is thus mainly considered a mean to alleviate symptoms, primarily by improving skeletal muscle function, but without the potential to reverse any structural changes within the pulmonary system which are seen in patients with COPD. The rationale for recommending exercise as a way to reduce symptom burden and increase quality of life, is based on the finding from the most recent Cochrane review. The authors stated that no additional studies comparing exercise with control were warranted, as exercise per se leads to improvements, regardless of the type of exercise.

The reasoning for not prescribing exercise more widely to patients with COPD is based on two assumptions: 1) new tissue cannot be formed in the adult lung, and 2) no consistent exercise training-induced changes in lung function have previously been documented.

However, de novo tissue formation has repeatedly been demonstrated in the adult lung, both in animals and humans, primarily in response to prolonged hypoxia and pneumonectomy. It has recently been reported that interval-based training counteracts the progressive loss of lung tissue in animal models of experimental COPD. The most likely stimulus is the mechanical strain, and if any measurable changes are to be induced by training, a high-intensity interval training (HIIT) scheme is preferable to be initiated in pulmonary rehabilitation.

An aspect of the progressive lung tissue loss in COPD that sets in from the very early stages of disease, seemingly before any ventilatory disturbance can be observed, is pulmonary vascular dysfunction and loss of pulmonary capillaries, driven by a seemingly disease-specific imbalance between angiogenetic and angiostatic processes in the pulmonary vasculature. Indeed, this is likely a mechanism that drives the concomitant loss of lung tissue, and also limits exercise capacity as the ability to expand the alveolar-capillary membrane though pulmonary capillary recruitment and distension becomes limited, thus critically attenuating oxygen uptake during exercise.

It is now well-established that the human lung conceals a diverse population of mechanosensitive progenitor and stem cells that appear to be dormant in COPD. Their reactivation by the stretch and strain as well as high vascular pressures associated with for example physical activity may likely explain why interval-based training has been found to counteract the progressive loss of lung tissue in animal models of experimental COPD. The investigators have developed in vitro protocols for assessing the regenerative capacity of the lung, and the next step will be to develop similar protocols for the human lung, both in the healthy state and from patients with COPD. In the present pilot study, the investigators will investigate the effects of an extensive high-intensity interval training (HIIT) on the regenerative capacity of the lung as determined by in vitro lung organoid culture and vascular tissue engineering 3D methods on patients with COPD on waiting list for lung volume reduction surgery.

Primary objective: To investigate whether prehabilitation with supervised HIIT while on waiting list for lung volume reduction surgery affects regenerative pathways in the lung. The investigators aim to determine if these effects can be detected non-invasively using blood biomarkers and spatial omics technologies to map region-specific molecular changes, cellular composition, and structural remodelling in lung tissue.

Secondary objectives: To determine whether an increase in blood volume is associated with an increased lung tissue mass (LTM), pulmonary blood volume (PBV), reduced symptom severity, and pulmonary diffusing capacity at rest and during exercise. To use explanted tissue to develop ex vivo models for disease and repair mechanisms.

Research hypotheses:

Primary: Prehabilitation while on waiting list for lung volume reduction surgery is superior to a non-exercise control group for increasing activating regenerative pathways in the lung with concomitant changes in LTM and PBV.

Secondary: Diffusing capacity during exercise and quality of life increases following prehabilitation with HIIT compared to a non-exercise control group. Finally, it is hypothesized that functional outcomes, V̇O2peak, body composition and cardiac output will be improved despite no/or limited changes in lung function in the HIIT group.

• Differential protein composition [Time frame: At surgery]
• Lung tissue protein composition [Time frame: At surgery]
• Serum protein profiles [Time frame: At surgery]
• Tissue niche and cellular composition [Time frame: At surgery]
• Translational regions [Time frame: At surgery]
• Inflammatory and remodelling factors (blood samples) [Time frame: From time of inclusion in the study and until surgery (up to 8 months)]
• Protein markers [Time frame: At surgery]
• Lung cell population [Time frame: At surgery]
• Lung tissue mass [Time frame: From inclusion in the study and until surgery (up to 8 months)]
• Pulmonary blood volume at rest [Time frame: From inclusion in the study and until surgery (up to 8 months)]
• DLNO at rest and during exercise [Time frame: From inclusion in the study and until surgery (up to 8 months)]
• DLNO during exercise [Time frame: From inclusion in the study and until surgery (up to 8 months)]