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

Patients with chronic obstructive lung disease (COPD) suffer from a progressive loss of lung function that leads to poor quality of life, and often invalidity and early death. Regular exercise can improve quality of life in these patients, but there is a lack in understanding the underlying mechanism of exercise-induced improvement in COPD and it is widely thought not to have any effect on the lung as such. In the present study, the investigators aim to investigate the impact of an extensive high-intensity interval training (HIIT)-based exercise scheme on the regenerative capacity of the lung in patients with COPD on waiting list for lung volume reduction surgery.

Design: Prospective randomized controlled clinical trial.

Intervention: 24 persons with COPD referred for lung volume reduction surgery will randomly be allocated (1:1) to prehabilitation with high intensity interval training (HIIT) or non-exercise control.

Outcomes: The primary outcome is differences in change in differential protein composition in distal lung tissue between HIIT and control groups post-intervention using spatial multimodal proteomics. Furthermore, lung tissue mass, protein composition (mass spectrometry and spatial omics e.g. MACSima), pulmonary blood volume, blood protein profile (biomarkers), diffusion capacity at rest and during exercise, oxygen consumption tests, body composition scan, distal airspace radii and physical functional tests will be measured before and after the intervention.

Perspective: This study may fundamentally change the view on the regenerative potential of the lungs in COPD.

Study Overview

• Status: Enrolling by invitation
• Conditions: COPD (Chronic Obstructive Pulmonary Disease)
• Intervention / Treatment: Behavioral: High Intensity interval training (HIIT)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Centre for Physical Activity Research, Copenhagen University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Men and women
• Referred for lung volume reduction surgery at Rigshospitalet because of emphysematous COPD.

Exclusion criteria

• Symptoms of ischaemic heart disease
• Known heart failure
• Unable to complete or understand HIIT training
• Claudication
• Symptoms of acute disease within 2 weeks prior to the study
• Known malignant disease
• Pregnancy
• Unstable cardiac arrhythmic disease

• Renal or liver dysfunction

  • Known chronic kidney or liver disease
  • Elevated creatinine, urea, alanine transaminase (ALAT), aspartate transaminase (ASAT), bilirubin, basic phosphatases at blood test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Controls will be encouraged to maintain current exercise habits for the duration of the study.
Experimental: Exercise group; The HIIT intervention group includes three supervised sessions per week over the period while on waitinglist for lung volumen reduction surgery. These will take place at either CFAS or at home and will be supervised	Behavioral: High Intensity interval training (HIIT); The HIIT intervention consist of 4 intervals with each lasting 4 minutes (4x4min). If a participant reports discomfort related to the length of the intervals or start to feel unmotivated by performing the same exercise, we will use another HIIT protocol: 10x1min. The 4x4min HIIT consists of a warm-up period of 10 minutes with a target heart rate at 60-70% of HRmax, followed by 4 HIIT intervals with a target HR ≥85%. The intervals are separated by three minutes of active rest, in which the HR should drop to 60% of maximum. Following this, a cool down period of three minutes at warm up intensity is performed. The 10x1min HIIT consists of a 10-minute warm-up period.The warm-up is followed by 10 intervals, each lasting 1 min at 100% of maximal workload, separated by three minutes of active rest, in which the HR should drop to 60% of maximum. Following the intervals, a cool down period of three minutes at warm up intensity is performed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differential protein composition	Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using spatial multimodal proteomics.	At surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differential protein composition	Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using mass spectrometry.	At surgery
Lung tissue protein composition	Differences in change in distal lung tissue protein composition pre- and post-HIIT intervention via mass spectrometry.	At surgery
Serum protein profiles	Differences in change in serum protein profiles between HIIT and control groups after intervention using mass spectrometry.	At surgery
Tissue niche and cellular composition	Tissue niche and cellular composition in the lung will be determined	At surgery
Translational regions	Healthy, diseased and transitional (''border zones'') regions in the lung will be deliniated/identified by using spation omic analysis. This will be done both at a gene level, protein level and glycosaminoglycan level.	At surgery
Inflammatory and remodelling factors (blood samples)	Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in blood samples measured by mass spectrometry	From time of inclusion in the study and until surgery (up to 8 months)
Protein markers	Protein markers will be identified by mass spectrometry and the difference in the spatial localisation of these will be identified between the groups after the intervention. This will be done using Pentachrome and/or multiplexed inmunofluorescence stainings.	At surgery
Lung cell population	Difference in change from baseline to follow-up between groups in lung cell populations by single cell-RNA sequencing.	At surgery
Lung tissue mass	Difference in change from baseline to follow-up between groups in total LTM (g)	From inclusion in the study and until surgery (up to 8 months)
Pulmonary blood volume at rest	Difference in change from baseline to follow-up between groups in pulmonary blood volume (mL) at rest	From inclusion in the study and until surgery (up to 8 months)
DLNO at rest and during exercise	Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) as a function of V̇O2 measured at rest, 60% of current maximal workload (relative), and at follow-up including 60% of maximal workload at baseline (absolute)	From inclusion in the study and until surgery (up to 8 months)
DLNO during exercise	Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during exercise at 60% of current maximal workload (relative)	From inclusion in the study and until surgery (up to 8 months)
DLNO during exercise	Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during exercise at 60% of the maximal workload measured at baseline (absolute)	From inclusion in the study and until surgery (up to 8 months)
Pulmonary blood volume / total blood volume ratio	Difference in change from baseline to follow-up between groups in pulmonary blood volume / total blood volume ratio	From inclusion in the study and until surgery (up to 8 months)
Health related quality of life	Difference in change from baseline to follow-up between groups in health-related quality of life - COPD Assessment Test (CAT) score, and St. George's Respiratory Questionnaire (SGRQ)	From enrollment until 3 months post-surgery
Extra cellular matrix structure	Extracellular matrix structure	At surgery
Inflammatory and remodelling factors (lung tissue)	Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in lung tissue measured by mass spectrometry	At surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tissue morphology	Difference in change from baseline to follow-up between groups in tissue morphology	At surgery
Mechanotransduction pathways	Detect increased activation of mechanotransduction pathways, marked by YAP/TAZ co-transcription factors, in lung tissue post-HIIT using spatial omics and advanced image analysis.	At surgery
Mesenchymal stromal cells	Difference in mesenchymal stromal cells from baseline until follow-up between the two groups	At surgery
Inflammatory patterns	Inflammatory patterns will be assessed understanding the difference in these inflammatory patterns from baseline until follow-up and the differences between the two groups	At surgery
Distal airspace dimensions	Difference in change from baseline to follow-up between groups in distal airspace dimensions (rAiDA and R0) as measured by AiDA	From enrollment to surgery
Neo-epitopes	Difference in change from baseline to follow-up between groups in neo-epitopes (degraded fragments of proteins) in lung tissue measured by mass spectrometry	At surgery
Changes in X-ray and electron-based imaging techniques	Difference in change from baseline to follow-up between groups in elemental and structural changes by X-Ray and electron-based imaging techniques	At surgery
Biophysical properties	Difference in change from baseline to follow-up between groups in biophysical properties (stiffness/elasticity) using tensile or atomic force microscopy (AFM	At surgery
Lung function	Differences in above measurements linked to lung function	At surgery
Cell activity	Differences in above measurements linked to cell activity	At surgery
Lobal lung tissue mass	Difference in change from baseline to follow-up between groups in lobar LTM (g)	From inclusion in the study until surgery (up to 8 months)
LTM/1.73 m2 BSA	Difference in change from baseline to follow-up between groups in LTM/1.73 m2 BSA (g/m2)	From inclusion in the study until surgery (up to 8 months)
Total blood volume	Difference in change from baseline to follow-up between groups in total blood volume	From inclusion in the study until surgery (up to 8 months)
DLNO during rest	Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during upright rest	From inclusion in the study and until surgery (up to 8 months)
DLCOc during rest	Difference in change from baseline to follow-up between groups in DL,CO,5s (mmol/(min kPa)) during upright rest	From inclusion in the study until surgery (up to 8 months)
Pulmonary capillary blood volume	Difference in change from baseline to follow-up between groups in pulmonary capillary blood volume (VC, mL) during upright rest	From inclusion in the study until surgery (up to 8 months)
Membrane diffusing capacity	Difference in change from baseline to follow-up between groups in alveolar-capillary membrane diffusing capacity (DM, mmol/(min kPa)) during upright rest	From inclusion in the study until surgery (up to 8 months)
Cardiac hemodynamics during exercise	Difference in change from baseline to follow-up between groups in cardiac output (L/min) during exercise at 60% of current maximal workload and 60% of baseline maximal workload, and during upright rest	From inclusion in the study until surgery (up to 8 months)
VO2 during diffusing capacity measurements	DL,CO,NO-based V̇O2 during exercise at 60% of current maximal workload and 60% of baseline maximal workload, and during upright rest	From inclusion in the study until surgery (up to 8 months)
Cardiac pulmonary exercise test outcomes	Difference in change from baseline to follow-up between groups in relative (mL/kg/min) V̇O2peak	From enrollment until 3 months post surgery
Handgrip-strength	Difference in change from baseline to follow-up between groups in hand-grip strength (kg)	From enrollment until 3 months post surgery
Sit-to-stand	Difference in change from baseline to follow-up between groups in numbers of completed 60 seconds sit-to-stand test (n)	From enrollment until 3 months post surgery
Body composition	Difference in change from baseline to follow-up between groups in body composition: total mass (kg)	From inclusion in the study and until surgery (up to 8 months)
Lung function	Difference in change from baseline to follow-up between groups in lung function: FEV1 (L and %pred)	From enrollment until 3 months post surgery
6-minutes walking distance	Difference in change in the distance (m) walked from baseline to follow-up between groups in a 6-minute walking test	From enrollment until 3 months post surgery
Exercise-induced cytokine response	Difference in change from baseline to follow-up between groups in exercise-induced cytokine responses (interleukin-6 (pg/mL)	From enrollment until 3 months post surgery
Mean bolus transit time - rest	Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (supine rest)	From inclusion in the study until surgery (up to 8 months)
Mean bolus transit time exercise	Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (adenosine infusion)	From inclusion in the study until surgery (up to 8 months)
Coronary flow reserve	Difference in change from baseline to follow-up between groups in global coronary flow reserve (mL/min)	From inclusion in the study until surgery (up to 8 months)
Pulmonary blood volume reserve	Difference in change from baseline to follow-up between groups in pulmonary blood volume reserve (mL)	From inclusion in the study until surgery (up to 8 months)
Ejection fraction	Difference in change from baseline to follow-up between groups in left ventricular ejection fraction (%)	From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - rest	Difference in change from baseline to follow-up between groups in cardiac output (L/min) (supine rest)	From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise	Difference in change from baseline to follow-up between groups in cardiac output (L/min)	From inclusion in the study until surgery (up to 8 months)
Total plasma volume	Difference in change from baseline to follow-up between groups in total plasma volume	From inclusion in the study until surgery (up to 8 months)
Red blood cells	Difference in change from baseline to follow-up between groups in red blood cells	From inclusion in the study until surgery (up to 8 months)
Coronary calcium score	Difference in change from baseline to follow-up between groups in coronary calcium score	From inclusion in the study until surgery (up to 8 months)
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: lipids (cholesterol (mmol/l)	From enrollment until 3 months post surgery
Lung resistance	Difference in change from baseline to follow-up between groups in resistance (Rrs, R5-R20) measured by IOS	From enrollment until 3 months post surgery
Lung reactance	Difference in change from baseline to follow-up between groups in reactance (Xrs, X5) measured by IOS	From enrollment until 3 months post surgery
Cardiac function and structure	Difference in change from baseline to follow-up between groups in cardiac structure and function including	From inclusion in the study until surgery (up to 8 months)
Progenitor cell changes	Difference in progenitor cells from baseline until follow-up between the two groups	At surgery
Cardio pulmonary test outcomes	Difference in change from baseline to follow-up between groups in absolute (mL/min) V̇O2peak	From enrollment until 3 months post surgery
Cardiac pulmonary exercise test outcomes	Difference in change from baseline to follow-up between group in ventilatory threshold (%)	From enrollment until 3 months post surgery
Cardiac pulmonary exercise test outcomes	Difference in change from baseline to follow-up between groups in ventilatory reserve (%)	From enrollment until 3 months post surgery
Body composition	Difference in change from baseline to follow-up between groups in body composition: total fat mass (kg and %)	From enrollment until 3 months post surgery
Body composition	Difference in change from baseline to follow-up between groups in body composition: lean body mass (kg)	From enrollment until 3 months post surgery
Body composition	Difference in change from baseline to follow-up between groups in body composition: fat percentage (%)	From enrollment until 3 months post surgery
Lung function	Difference in change from baseline to follow-up between groups in lung function: FVC (L and %pred)	From enrollment until 3 months post surgery
Lung function	Difference in change from baseline to follow-up between groups in lung function: RV (L and %pred)	From enrollment until 3 months post surgery
Lung function	Difference in change from baseline to follow-up between groups in lung function: , TLC (L and %pred)	From enrollment until 3 months post surgery
Lung function	Difference in change from baseline to follow-up between groups in lung function: single-breath diffusion capacity to carbon monoxide (mmol/(min kPa) and %pred)	From enrollment until 3 months post surgery
Exercise-induced cytokine response	Difference in change from baseline to follow-up between groups in tumour necrosis factor-α (pg/mL)	From enrollment until 3 months post surgery
Exercise-induced cytokine response	Difference in change from baseline to follow-up between groups in C-reactive protein (μg/mL)	From enrollment until 3 months post surgery
Exercise-induced cytokine response	Difference in change from baseline to follow-up between groups in interleukin-8 (pg/mL)	From enrollment until 3 months post surgery
Exercise-induced cytokine response	Difference in change from baseline to follow-up between groups in interleukin-10 (pg/mL))	From enrollment until 3 months post surgery
Cardiac dynamics - rest	Difference in change from baseline to follow-up between groups in heart rate (bpm) (supine rest)	From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - rest	Difference in change from baseline to follow-up between groups in stroke volume (mL) (supine rest)	From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise	Difference in change from baseline to follow-up between groups in cardiac output (L/min) (adenosine infusion)	From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise	Difference in change from baseline to follow-up between groups in stroke volume (mL) (adenosine infusion)	From inclusion in the study until surgery (up to 8 months)
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: LDL (mmol/l)	From enrollment until 3 months post surgery
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: HDL (mmol/l))	From enrollment until 3 months post surgery
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: HbA1C (mmol/l)	From enrollment until 3 months post surgery
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: HsCRP (mg/L)	From enrollment until 3 months post surgery
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: pro-BNP (pmol/L)	From enrollment until 3 months post surgery
Blood samples	Difference in change from baseline to follow-up between groups in blood samples: TSH (10-3 IU/L)	From enrollment until 3 months post surgery

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Lund University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: January 6, 2026
• First Posted (Actual): January 15, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Physical Conditioning, Human; Exercise; High-Intensity Interval Training
• Other Study ID Numbers: H-25061713

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No