**3. Pathophysiology of COPD and AECOPD**

COPD is the result of a chronic inflammation in the airways. The inflammation is initiated by chronic exposure to exogenic toxins (e.g. cigarette smoke) which is causing damage to the airway epithelium and is activating the innate immune system giving a rapid, nonspecific response [20, 21]. Of the innate immune response the neutrophillic inflammation is most prominent in COPD. The cells of the innate immune system activate the adaptive immune system, of which CD8+-cells, CD4+ Thelper1 cells and B-cells have an important role in COPD. This activation of the adaptive immune response is the beginning of a cascade which causes extensive chronic inflammation, oxidative stress and remodeling, resulting in destruction of alveolar space and deposition of connective tissue in the subepithelium and adventitium of the airway wall [22]. The degree of chronic inflammation in COPD correlates with the severity of airflow limitation. This is supported by a correlation which is seen between the severity of obstruction and presence of CD8+-cells and B-cells in the small conducting airways [22] and the presence of neutrophils in sputum [23]. Also, bacterial colonization is more frequently observed in patients with severe to very severe COPD, suggesting that bacterial colonization induces inflammation and contributes to the progression of COPD [24, 25]. The existence of the chronic inflammation and oxidative stress is supported by the presence of oxidants and numerous pro-inflammatory cytokines in the airways and serum. Compared to healthy controls, sputum specimens of patients with stable COPD and AECOPD show increased numbers of neutrophils and increased levels of pro-inflammatory cytokines like interleukin-6 (IL-6) and interleukin-8 (IL-8) [21, 23, 26-29]. During an AECOPD neutrophils, IL-6 and IL-8 are also increased in serum [27, 30, 31]. Interleukin-6 is a cytokine released during initial immune response by different cell types of the native immune system, like macrophages. It induces hepatic acute phase response during inflammation [32] which in turn increases production of C-reactive protein (CRP). Interleukin-6 is also a growth factor for T- and B-cells [33]. Interleuking-8 is released by a variety of cell types involved in inflammation, like endothelial cells, fibroblasts and monocytes [34]. It is a potent neutrophil chemotactic and activating factor [34]. The presence of the increased inflammation in serum both during stable state and AECOPD may be explained by the "overspill theory", in which the local inflamma‐ tory processes in the lung "spill over" to the systemic circulation [35]. It is therefore thought that disease activity of COPD can be measured in serum by biomarkers. Exhaled breath condensate (EBC) components are thought to reflect the physiological state of lining fluid of the airways. It's a non-invasive mean of obtaining information on oxidative stress and inflammation in the airways. Hydrogen peroxide (H2O2, a precursor of potent oxidants OH and HOCl) and 8-isoprostane (formed by the free radical peroxidation of arachidonic acid) are EBC oxidative stress biomarkers proven to be elevated in patients with COPD during stable state and during exacerbations [31, 36-38]. Heme-oxygenase-1 (HO-1) is an inducible catalyzer of the degradation of heme to biliverdin which is thought to provide protection from oxidative stress. It is decreased in ex-smokers with COPD compared to control subjects [39] but increased during severe exacerbations [29], in healthy smokers and current smokers with COPD [40].
