Background

The severity of Chronic Obstructive Pulmonary Disease (COPD) is usually described in terms of forced expiratory volume in one second (FEV1) and number of exacerbations. However, COPD is a complex disease with different ways of expression, involving pulmonary symptoms, extra pulmonal manifestations and comorbidities, which altogether affect the patient by contributing to reduced functional capacity, increased shortness of breath, reduced health-related quality of life and increased mortality. Systemic inflammation is common in COPD and can potentially constitute a link between the lungs and other organs.  

The aim of this thesis was to broaden the aspects of COPD severity beyond FEV1 and exacerbations by studying fatigue, the role of vitamin D, nutritional factors, systemic inflammation and peripheral muscle function in patients with COPD.   

Methods and Results

In paper I, we included 101 patients with COPD, and 34 control subjects. Assessment of experience of fatigue, functional limitation due to fatigue, and the relationships to physiological, psychological and situational variables and quality of life (QoL) were evaluated.   We found that experience of fatigue was highly prevalent (72% versus 56% in control subjects) and a troublesome symptom in COPD. Patients with COPD and fatigue had lower lung function, shorter walking distance, more dyspnoea, anxiety and depressive symptoms and poorer health status compared to patients without fatigue (all p < 0.01). Several contributing factors were identified to experience of fatigue and functional limitations of fatigue with dyspnoea, depressive symptoms and insomnia as the most prominent factors. No clear association with systemic inflammation was found.  

Paper II evaluated vitamin D status in 66 patients with advanced COPD (28 with long-term oxygen therapy (LTOT)) and 47 control subjects. 25-hydroxyvitamin 25(OH)D were deter-mined in early fall in a short period of seven weeks. Questionnaires about COPD symptoms, general health, lifestyle, dietary habits and QoL were answered. Lung function tests and blood sampling including systemic inflammatory markers, carotenoids and protein carbonylation (PC) were assessed. The peak annual 25(OH)D of COPD patients was significantly lower than in the control subjects, but there was no significant difference between COPD patients with and without LTOT. Among vitamin D-deficient COPD patients, 25(OH)D correlated positively with lung function, blood oxygenation, food portion size, Mediterranean Diet Score and Ultra-violet Score and negatively with dyspnoea and DOSE-index, a composite index for COPD se-verity. Ongoing vitamin D supplementation was the single most important intervention to maintain 25(OH)D levels <50 nmol/L.  

In paper III, we evaluated in the same cohort as paper II oxidative damage and levels of carotenoids. Patients with COPD (±LTOT) did not demonstrate increased oxidative damage. Com-pared with the control group, levels of several carotenoids were significantly lower in COPD, and the diet contained significantly less fruit and vegetables. Lycopene correlated positively with saturation and lutein correlated positively with some inflammatory markers but negatively with IL-6, an important marker for systemic inflammation. The study highlights the importance of dietary factors in COPD.   

In paper IV, 32 patients with COPD answered questionnaires, and were subjected to lung function tests and blood analysis including systemic inflammatory markers. Magnetic resonance imaging (MRI) for analysis of whole-body and thigh muscle composition was performed. Bioenergetics in the resting thigh muscle, (PCr/Pi ratio), were analysed using 31phosphorus magnetic resonance spectroscopy (31P-MRS). We found that adverse muscle composition was common in the COPD group. Clinical characteristics reflecting COPD severity were all associated with a raise of the PCr/Pi ratio in the thigh muscle. Increased MFIa correlated positively to systemic inflammatory markers, negative to physical activity and PCr/Pi ratio. We compared the COPD group with a virtual control group from UK Biobank (n= 3200).  

Conclusions

Severe COPD is much more than airway obstruction and exacerbations. The presence of fatigue is associated, as well as vitamin D status and nutritional factors, with important clinical out-comes reflecting COPD severity. Adverse muscle composition is common in COPD and there seems to be a link between systemic inflammation, muscle fat infiltration and bioenergetics. 

Background

Chronic obstructive pulmonary disease (COPD) is a progressive disorder with phenotypic heterogeneity, which includes nonreversible airflow limitation, chronic airway inflammation and systemic expression. COPD extends beyond the lungs to skeletal muscle, metabolism, and immune function. Oxidative stress and lysosomal impairment are among the key processes that may bridge local tissue damage with systemic effects. Despite several lines of investigations, the relationship between oxidative stress, systemic inflammation, muscle pathology and vitamin D deficiency to influence outcome in COPD remains to be fully addressed.

Aims

The general aim of this thesis was to study molecular, cellular and systemic processes in COPD with emphasis on oxidative stress, lysosomal stability, immune cell function, skeletal muscle changes and vitamin D status. Complementing mechanistic in vitro and ex vivo approaches with imaging and biomarker readouts; the thesis aimed to unravel disease progression pathways and unveil potential therapeutic targets.

Methods and Results

Paper I

Study of type II alveolar-like epithelial cells exposed to oxidants. Reactive oxygen species (ROS) induced ferritin degradation and lysosomal iron release to induce epithelial–mesenchymal transition (EMT). Such effects were mitigated by antioxidants and lysosomal stabilizers, which provide support to the implication of the lysosomal–iron axis in airway remodeling.

Paper II

Study of alveolar macrophages in Broncho-Alveolar Lavage Fluid (BALF) from patients with inflammatory disorders demonstrating Chronic Airway Limitation (CAL) on dynamic spirometry and controls. The macrophages of the patients with CAL were more sensitive to oxidant-mediated lysosomal membrane permeabilization (LMP) than controls. LMP was associated with the extent of airflow limitation, consistent with lysosomal fragility as a pathogenic determinant in COPD.

Paper III

Investigated skeletal muscles in COPD patients and controls by MRI together with 31P-MRS. Individuals with COPD demonstrated severe myosteatosis, dysfunctional oxidative capacity and reduced functional performance. Increased general systemic inflammation was associated with adverse muscle composition indicative of a lung-muscle inflammatory axis.

In Paper IV

We examined 111 patients with GOLD E COPD and found that those with serum 25- hydroxyvitamin D [25(OH)D] concentrations <50 nmol/L were more symptomatic, had higher levels of high-sensitivity C-reactive protein (hsCRP) and experienced significantly more exacerbations than those who had a serum concentration ≥50 nmol/L. Decreased 25(OH)D was associated with worse symptoms, increased inflammation, and more frequent exacerbation, emphasizing the clinical significance of vitamin D deficiency in severe COPD.

Conclusion

This thesis shows that COPD involves a cascade from oxidative stress and lysosomal damage in epithelial cells and macrophages, to systemic inflammation, skeletal muscle dysfunction and susceptibility for exacerbations associated with vitamin D deficiency.