Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, characterized by persistent airflow limitation, chronic inflammation, and increased oxidative stress. Despite optimal pharmacological treatment, many patients continue to experience symptoms, reduced exercise capacity, and frequent exacerbations. Pulmonary rehabilitation (PR) is an evidence-based, non-pharmacological intervention that improves symptoms, functional capacity, quality of life, and survival in patients with COPD; however, its biological effects on inflammatory and oxidative stress pathways remain insufficiently defined.

This study aims to evaluate the effects of pulmonary rehabilitation on systemic inflammation and oxidative stress in patients with stable COPD. Serum levels of pro-inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α]) and the epithelial alarmin interleukin-33 (IL-33), which is released in response to airway epithelial injury, as well as nuclear factor erythroid 2-related factor 2 (NRF-2) gene and/or protein expression as a key regulator of antioxidant defense, will be measured before and after a standardized pulmonary rehabilitation program. By assessing changes in these biomarkers, this study seeks to determine whether pulmonary rehabilitation exerts disease-modifying effects beyond symptomatic improvement and functional outcomes.

The findings are expected to provide novel insights into the biological mechanisms of pulmonary rehabilitation and to support its role as a targeted, cost-effective intervention in the comprehensive management of COPD.

Inclusion Criteria:

• Adults aged 40-80 years with a diagnosis of stable COPD
• Airflow limitation defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (forced expiratory volume in 1 second / forced vital capacity [FEV₁/FVC] < 70% and forced expiratory volume in 1 second [FEV₁] < 70% predicted)
• Former smokers with a smoking history of at least 10 pack-years
• Clinically stable disease at the time of enrollment
• Ability and willingness to participate in the pulmonary rehabilitation program
• Provision of written informed consent

Exclusion Criteria:

• Current smokers
• History of acute COPD exacerbation or respiratory infection within the past 6 weeks
• Presence of other chronic lung diseases (e.g., bronchiectasis, interstitial lung disease, asthma)
• Active malignancy
• Severe or uncontrolled cardiovascular disease, including recent acute myocardial infarction or malignant arrhythmias
• Neurological, orthopedic, or psychiatric conditions that preclude objective functional assessment or participation in exercise training
• Use of antioxidant or vitamin supplementation within the past 4 weeks
• Determination by a cardiologist that participation in an exercise-based rehabilitation program is not medically appropriate

Patients aged 40 to 80 years with a diagnosis of stable COPD, defined according to the GOLD criteria (FEV₁/FVC < 70% and FEV₁ < 70% predicted), who are former smokers with a smoking history of at least 10 pack-years, and who are referred to the pulmonary rehabilitation program of our institution, will be consecutively enrolled in the study.

All IPD used in the results publication