The cellular components of COPD

Studies suggest that the inflammation in the lungs of COPD patients appears to be a magnification of the normal inflammatory response following exposure to insults such as cigarette smoke (Pauwels et al., 2001). The first line of defence in the face of the inhaled insults is the epithelium, which produces inflammatory mediators initiating the chemotaxis and accumulation of a selection of inflammatory cells including neutrophils, macrophages and lymphocytes. Furthermore, oxidative stress and proteases further amplify this inflammatory response and drive the classic pathological changes seen in COPD patients.

However, COPD is a complex disease; therefore the types of inflammatory cells involved and their patterns or sequences of appearance are relatively poorly understood. Studies examining

34 the lungs of COPD patients show infiltration by immune cells including CD8+ T-cells and a large number of neutrophils and macrophages (Grumelli et al., 2004). Macrophages are considered a key cell in the pathogenesis of COPD since they are located in areas of active tissue destruction (Barnes, 2004).

Figure 1.2 – Cigarette smoke and inflammatory processes in the lung.

1.3.4.1 The epithelium

As the first line of defence against invading pathogens is the barrier between host and the environment, the epithelium plays a major role in responses to inhaled insults such as cigarette smoke. An important role in the defence of the airways is the production of mucus

35 from goblet cells to trap bacteria and inhaled particulates (Adler & Li, 2001). Various hypotheses have been suggested for a role of the epithelium in initiating and maintaining the inflammatory responses following cigarette smoke inhalation. Epithelial cells are activated by cigarette smoke to produce inflammatory mediators, including TNF-α, IL-1β, GM-CSF, and IL-8 (Mio et al., 1997; Hellermann et al., 2002; Floreani et al., 2003). Primary human bronchial epithelial cells have been shown to release increased levels of inflammatory chemokine IL-8 in response to treatment with cigarette smoke condensate (Fields et al., 2005). In addition, human bronchial epithelial cells have also been demonstrated to be responsive to very low levels of IL-1β, when examining IL-8 release in culture (Coulter et al., 1999). Furthermore, primary epithelial cells from patients with COPD have been demonstrated to release more IL-8 than those from smokers without airflow limitation (Schulz et al., 2004). These findings suggest that the epithelium plays an important role as the first line of defence by producing inflammatory mediators required for the chemotaxis of immune cells into the lung.

1.3.4.2 Neutrophils

Neutrophils are one of the dominant cell types recruited into the lung in COPD, however, their role in this disease is not yet fully understood. The percentage of neutrophils in samples taken from COPD patients are increased with GOLD stage (Singh et al., 2010). Studies have shown increased numbers of activated neutrophils are found in sputum and BAL fluid of patients with COPD (Lacoste et al., 1993; Keatings et al., 1996), however, this increase is not mirrored in the airways or lung parenchyma (Finkelstein et al., 1995). Smoking may also increase neutrophil retention in the lung (MacNee et al., 1989). Furthermore, the literature suggests that neutrophils recruited to the airways of COPD patients are activated, based on

36 the increased concentrations of granule proteins, such as myeloperoxidase and human neutrophil lipocalin, in the sputum supernatant (Keatings & Barnes, 1997; Yamamoto et al., 1997; Peleman et al., 1999).

Although neutrophils are believed to be predominantly involved in the control of bacterial and viral infections of the lung (Laws et al., 2010; Tate et al., 2009), they have also been shown to provide a source of serine proteases such as neutrophil elastase (NE), matrix metalloproteinases (MMPs) and cathepsins, which may contribute to alveolar destruction.

These serine proteases also potentiate mucus hypersecretion (Geraghty et al., 2007).

1.3.4.3 Macrophages

Macrophages are derived from blood borne monocytes and mature into macrophages when they enter tissue. In the lung they function as long-lived effector cells. They play a crucial role in the pathogenesis of COPD defending against endogenous and exogenous stimuli.

Furthermore, they produce mediators to initiate or alternate the actions of other local cells as well as being responsible for the clearance of apoptotic neutrophils (Tetley, 2002). The numbers of alveolar macrophages are increased between 5 – 10 fold in the airways, parenchyma, bronchoalveolar lavage (BALF) and sputum of smokers and patients with COPD (Finkelstein et al., 1995). This is further supported by the correlation between macrophage numbers in the airways and COPD disease severity (Di Stefano et al., 1998).

Examination of macrophages taken from smokers identified that there are morphological and functional changes in this cell type (Harris et al., 1970).

37 Macrophages are activated upon exposure to cigarette smoke to release inflammatory mediators, thus providing a cellular mechanism that links smoking with inflammation in COPD. Alveolar macrophages also secrete elastolytic enzymes, including MMP-2, MMP-9, MMP-12, cathepsins K, L, and S, and neutrophil elastase taken up from neutrophils (Punturieri et al., 2000; Russell et al., 2002). Another function of macrophages is to ingest apoptotic cells; therefore, the reported decreased phagocytic activity of alveolar macrophages in COPD patients may explain the increased numbers of neutrophils in the airways (Hodge et al., 2003).

1.3.4.4 T Lymphocytes

The role of T lymphocytes in COPD is a relatively unknown area. Recent studies have demonstrated an increase in the total numbers of T lymphocytes; particularly the sub-type cluster of differentiation (CD) 8⁺ T cells, in lung parenchyma and airways of patients with COPD (Finkelstein et al., 1995; Saetta et al., 1999; Retamales et al., 2001). Furthermore, a correlation between the numbers of T cells, the degree of airflow obstruction and the amount of alveolar destruction exists. An increase in the absolute number of CD4⁺ T cells has been shown in COPD patients, but the ratio of CD4⁺/CD8⁺ cells is reversed in COPD. This finding has been demonstrated in smokers with COPD but not smokers that do not show signs of airflow limitation (Majo et al., 2001).

Dendritic cells may migrate from the airways to regional lymph nodes and stimulate proliferation of CD8⁺ and CD4⁺ T cells. CD8⁺ T cells are typically increased in airway infections, and it is possible that bacterial and viral pathogens, occupying the lower respiratory tract of COPD patients, are responsible for this inflammatory response (Hill et al.,

38 1999). Current dogma suggests that the epithelium plays a role in the recruitment of cells into the airways in response to oxidative DNA damage to lung epithelial barrier cells. One possible hypothesis is that upon damage of the lung epithelial barrier cells, dendritic cells mistake these as foreign, leading to the clonal expansion of CD8⁺ T cells upon entering the lymph nodes. This in turn leads to proliferation of cytotoxic CD8⁺ T cells and the subsequent release of perforin and granzyme, which can attack altered epithelial cells thus propagating the immune response (Tzortzaki & Siafakis, 2009).