Chronic Obstructive Pulmonary Disease: Pathogenesis

Figure 1: Pathogenesis of COPD

http://advanceweb.com/web/focus_on_copd/article2.html

Although COPD is mostly caused by cigarette smoking, environmental factors such as indoor air pollution and prolonged occupational exposure to dust and fumes can also contribute to its pathogenesis. In rare cases, COPD can be caused by a genetic abnormality called alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin is an antiprotease enzyme inhibitor that normally prevents the destruction of lung tissue by other enzymes (Coughlin, 2007). The precise pathogenesis of COPD is not fully known, but it is anticipated that interactions occur among different mechanisms of airway inflammation, protease – antiprotease imbalance, oxidative stress and apoptosis (Cerveri, & Brusasco, 2010). Being an irreversible disease, lung inflammation in COPD patients does not stop but continues for many years even after smoking cessation (Roth, 2008). This may be due to the lung not being able to remove some of the harmful components of cigarette smoke, or not being able to repair the damaged pulmonary tissues (Roth, 2008). Stopping smoking does, however, affect the progression of the disease and is associated with a decrease in cough and sputum production. Immediately following cessation, a small improvement in lung function was noted, after which lung function then declined, but at a rate similar to that of a non-smoker (Spurzem, Stephen, & Rennard, 2005).

Inflammation

Clients with chronic obstructive pulmonary disease have inflammation present in the lower respiratory tract, which becomes acutely worse during exacerbations. In stable COPD, there is accumulation of macrophages, neutrophils and lymphocytes, particularly CD8+ T-lymphocytes. Generally, the degree of infiltration with activated immune cells progressively increases as the disease worsens (Roth, 2008).

Under normal circumstances, inhaled irritant particles would undergo phagocytosis by macrophages and subsequently be destroyed. This is an important defence mechanism where toxic particles are neutralized and cleared from the lung. In smokers, evidence suggests that macrophage clearance from the lungs does not match macrophage accumulation (Tetley, 2002). Thus, particle-laden macrophages do not exit the lungs by way of mucus or lymphatic system, as would be expected.

Once the inflammatory response is set in motion, 3 types of damage occur to the lung: disruption of the alveolar walls, mucus hypersecretion contributing to airway obstruction, and fibrosis of the bronchioles. The pulmonary vasculature is also affected by inflammatory processes in COPD, which result in loss of capillary bed, luminal narrowing, and ultimately increased pulmonary vascular pressure that appears first with exercise and then at rest as the disease progresses (Scanlon, 2004).

Protease and Antiprotease Imbalance

Figure 2: Alpha-1 antitrypsin deficiency in emphysema
http://medicinembbs.blogspot.ca/2011/02/pathogenesis-of-emphysema.html

Emphysema is characterized by destruction of the alveolar wall, which is now widely accepted to result from an excess of proteolytic activity (Spurzem et al., 2005). There can be increased production or activity of proteinases, or inactivation or reduced production of antiproteinases (American Thoracic Society, 2012). The major serine proteinases produced by neutrophils include elastase, cathepsin G, proteinase-3, and at least two metalloproteinases – MMP8 and MMP9 (Tetley, 2002). The ones produced by macrophages are cathepsins B, L and S, and various other matrix metalloproteinases (MMP) (reference).

When neutrophils and macrophages are activated, these enzymes are released and are able to degrade most extracellular matrix components (Tetley, 2002). For example, neutrophil elastase contributes to alveolar wall destruction, and has also been found to be a very potent inducer of mucus secretion and goblet cell metaplasia through activation of the epidermal growth factor receptor (Sommerhoff, Nadel, Basbaum, & Caughey, 1990; Spurzem et al., 2005). Previous studies conducted by Gross and others have demonstrated that enzymes with elastolytic activity induced emphysema, whereas proteolytic enzymes lacking the ability to degrade elastin did not induce emphysema (Gross, Babyak, Tolker, & Kaschak, 1964; Janoff et al., 1977).

The major antiproteinases involved in COPD include α1-antitrypsin, secretory leukoproteinase inhibitor and tissue inhibitors of MMPs (American Thoracic Society, 2012; Dekhuijzen et al., 1996). As previously mentioned, congenital deficiency of α1-antitrypsin contributes to an individual developing COPD since it disrupts the protease-antiprotease balance. Additionally, the balance between proteases and antiproteases may be disrupted by the inflammatory process mentioned above. The production of oxygen reactive species (ROS) from the inflammatory response in addition to those derived from cigarette smoke or other irritants result in antiproteases becoming vulnerable to oxidation (Spurzem & et al., 2005). Oxidation of α-1 protease inhibitor makes it ineffective as an antiprotease. Therefore, a positive feedback loop is created in which inflammation induces these imbalances, and the imbalances promote more inflammation (Scanlon, 2004). The following figure displays the disproportion between proteases and antiproteases:

Figure 3: Protease-antiprotease imbalance in COPD

Barnes, P.J. (2000). Chronic obstructive pulmonary disease. New England Journal of Medicine, 4(343), 269-280.

Oxidative Stress

As previously mentioned, cigarette smoke contains highly reactive oxygen species while the inflammatory response in individuals with COPD also generates them, which leads to tissue damage. Oxidative stress occurs when ROS are produced in excess of endogenous antioxidant defence mechanisms (Park, Ryter, & Choi, 2007). This results in oxidization of a variety of biological molecules, such as lipids, proteins and deoxyribonucleic acid (DNA). Consequently these can lead to cell dysfunction or death, damage to extracellular matrix, and inactivation of key anti-oxidant defences (or activation of proteinases) (American Thoracic Society, 2012).

Different markers of oxidative stress are found in increased amounts in the lungs and exhaled air breath condensate of COPD patients, as well as urine of smokers. These markers are hydrogen peroxide, nitric oxide and lipid peroxidation products (American Thoracic Society, 2012).

Apoptosis
A regulated form of cell death, or apoptosis, may play an important role in pathogenesis of COPD. Lung tissue and airways of individuals with COPD has shown to have increased numbers of apoptotic cells relative to normal lungs or even smokers without COPD (Park et al., 2007). Mechanisms independent of inflammation may contribute to the development of emphysema through apoptosis of endothelial cells of alveolar walls.

Other changes in COPD

Mucus hypersecretion and ciliary dysfunction (American Thoracic Society, 2012; Spurzem et al., 2005)

Normal pseudostratified ciliated epithelium of the airway is replaced by goblet cells, and in the later stages by squamous metaplasia
Enlargement of mucous glands – mucus production that is abnormal in quality and increased in quantity
Cilia that is responsible for mucus clearance is disrupted

Fibrosis and airflow limitation (American Thoracic Society, 2012)

Smaller airways (<2 mm in diameter) accumulate mesenchymal cells, which produce collagenous extracellular matrix → fibrosis and narrowing
Mucus hypersecretion also contributes to airflow limitation

Gas-Exchange abnormalities

Occurs in advanced disease and is characterized by arterial hypoxemia (↑O₂) with or without hypercapnia (↑CO₂).
Abnormal gas exchange due to abnormal ventilation-perfusion (V/Q) ratio

Pulmonary Hypertension

Also occurs in advanced disease, normally after development of severe gas exchange abnormalities.
Contributing factors: vasoconstriction (mostly hypoxic origin), endothelial dysfunction, remodelling of pulmonary arteries and destruction of the pulmonary capillary bed, which may lead to right ventricular hypertrophy and cor pulmonale (right heart failure)

Systemic Effects
The most likely cause of death for individuals with COPD is cardiovascular disease. The mechanisms that account for this risk are not well understood. Clients with COPD have increased levels of C-reactive protein, which is a known factor for the development of atherosclerosis (Spurzem et al., 2005). Lung inflammation may also result in certain circulating cytokines (ie. IL-6), which can lead to a hypercoagulable state. This would predispose an individual to thrombotic complications.

Acute Exacerbations
Acute exacerbations in COPD are characterized by changes in inflammatory cellular pattern. There is a further increase in eosinophils and/or neutrophils as well as various inflammatory mediators (Papi, Luppi, Franco, & Fabbri, 2005). The increase in airway inflammation could lead to increased bronchial tone, increased bronchial wall edema, and mucus hypersecretion. These processes contribute to worsening of V/Q mismatch, and expiratory flow limitation. Furthermore, alveolar hypoventilation and respiratory muscle fatigue add to hypoxemia, hypercapnia and respiratory acidosis, which if left untreated, will lead to respiratory failure and death (American Thoracic Society, 2012).