COPD is characterized by pathologic changes in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature. Chronic inflammation in the lung from repeated exposure to noxious particles and gases is primarily responsible for these changes. An imbalance between proteinases and antiproteinases in the lung and oxidative stress are also thought to be important in the pathogenesis of COPD. These processes may be a result of ongoing inflammation or may arise from environmental (e.g., oxidants in cigarette smoke) or genetic (e.g., AAT deficiency) factors (Fig. 15-1). In addition to these destructive processes, chronic inflammation and exposure to noxious particles and gases disrupts or impairs the normal protective and repair mechanisms.
Inflammation is present in the lungs of all smokers. It is unclear why only 15% to 20% of smokers develop COPD, but susceptible individuals appear to have an exaggerated inflammatory response.5 The inflammation of COPD differs from that seen in asthma, so the use of anti-inflammatory medications and the response to those medications are different. The inflammation of asthma is mainly mediated through eosinophils and mast cells. In COPD, the primary inflammatory cells include neutrophils, macrophages, and CD8+ T lymphocytes. Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-a (TNF-a). Various proteinases, such as elastase, cathepsin G, and pro-teinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures.
FIGURE 15-1. Pathophysiology of COPD.
a The physiologic abnormalities usually develop in this order.
Proteinases and antiproteinases are part of the normal protective and repair mechanisms in the lungs. The imbalance of proteinase-antiproteinase activity in COPD is a result of either increased production or activity of destructive proteinases or inac-tivation or reduced production of protective antiproteinases. AAT (an antiproteinase) inhibits trypsin, elastase, and several other proteolytic enzymes. Deficiency of AAT
results in unopposed proteinase activity, which promotes destruction of alveolar walls and lung parenchyma, leading to emphysema.
Markers of oxidative stress (e.g., hydrogen peroxide, nitric oxide, and isoprostane
F a-III) have been found in the epithelial fluid, breath, and urine of cigarette smokers
and patients with COPD. Increased oxidative stress contributes to COPD in a variety of ways. Oxidants (e.g., reactive oxygen species, superoxide, and nitric oxide) can react with and damage a variety of molecules leading to cell dysfunction and damage to the lung extracellular matrix. Oxidative stress promotes inflammation and contributes to the proteinase-antiproteinase imbalance by reducing antiproteinase activity. In addition, oxidants constrict airway smooth muscle, contributing to reversible airway narrowing.
In the central airways (the trachea, bronchi, and bronchioles greater than 2 to 4 mm in internal diameter), inflammatory cells and mediators stimulate mucus-secreting gland hyperplasia and mucus hypersecretion. Mucus hypersecretion and ciliary dysfunction lead to chronic cough and sputum production. The major site of airflow obstruction is the peripheral airways (small bronchi and bronchioles with an internal diameter less than 2 mm). Three mechanisms are postulated to be involved in the narrowing of these small airways. Airways may be blocked by inflammatory exudates and mucus hypersecretion. Loss of elasticity and destruction of alveolar attachments leads to loss of support and closure of small airways during expiration. Infiltration of inflammatory cells, increased smooth muscle tissue, and fibrosis cause thickening of airway walls. Of these mechanisms, the structural changes in the airway walls are the most important cause of fixed airflow obstruction.
As airflow obstruction worsens, the rate of lung emptying is slowed and the interval between inspirations does not allow expiration to the relaxation volume of the lungs. This leads to pulmonary hyperinflation, which initially only occurs during exercise, but later is also seen at rest. Hyperinflation contributes to the discomfort associated with airflow obstruction by flattening the diaphragm and placing it at a mechanical disadvantage.
In advanced COPD, airflow obstruction, damaged bronchioles and alveoli, and pulmonary vascular abnormalities lead to impaired gas exchange. This results in hypoxemia and eventually hypercapnia. Hypoxemia is initially present only during exercise but occurs at rest as the disease progresses. Inequality in the ventilation-to-perfusion ratio (Va/Q) is the major mechanism behind hypoxemia in COPD. As hypoxemia worsens, the body may compensate by increasing the production of eryth-rocytes in an attempt to increase oxygen delivery to tissues.
Pulmonary hypertension develops late in the course of COPD, usually after the development of severe hypoxemia. It is the most common cardiovascular complication of COPD and can result in cor pulmonale, or right-sided heart failure. Hypox-emia plays the primary role in the development ofpulmonary hypertension by causing vasoconstriction ofthe pulmonary arteries and promoting vessel wall remodeling. Destruction of the pulmonary capillary bed by emphysema further contributes by increasing the pressure required to perfuse the pulmonary vascular bed. Cor pulmon-ale is associated with venous stasis and thrombosis that may result in pulmonary embolism. Another important systemic effect is the progressive loss of skeletal muscle mass, which contributes to exercise limitations and declining health status. These extrapulmonary effects may contribute to disease severity and should not be overlooked.
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