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INTRODUCTION

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Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by airflow limitation that is not fully reversible (http://www.goldcopd.com/). COPD includes emphysema, an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not included within COPD.

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COPD is the third leading cause of death and affects >10 million persons in the United States. COPD is also a disease of increasing public health importance around the world. Estimates suggest that COPD will rise from the sixth to the third most common cause of death worldwide by 2020.

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PATHOGENESIS

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Airflow limitation, the major physiologic change in COPD, can result from both small airway obstruction and emphysema. As described below, small airways may become narrowed by cells (hyperplasia and accumulation), mucus, and fibrosis. Of note, activation of transforming growth factor β (TGF-β) contributes to airway fibrosis, while lack of TGF-β may contribute to parenchymal inflammation and emphysema. Largely due to greater similarity of animal air spaces than airways to humans, we know more about mechanisms involved in emphysema than small airway obstruction.

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The dominant paradigm of the pathogenesis of emphysema comprises four interrelated events (Fig. 314-1): (1) Chronic exposure to cigarette smoke leads to inflammatory and immune cell recruitment within the terminal air spaces of the lung. (2) These inflammatory cells release elastolytic and other proteinases that damage the extracellular matrix of the lung. (3) Structural cell death (endothelial and epithelial cells) occurs directly through oxidant-induced cigarette smoke damage and senescence as well as indirectly via proteolytic loss of matrix attachment. (4) Ineffective repair of elastin and other extracellular matrix components result in air space enlargement that defines pulmonary emphysema.

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FIGURE 314-1

Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke, inflammatory cells are recruited to the lung; they release proteinases in excess of inhibitors, and if repair is abnormal, this leads to air space destruction and enlargement or emphysema. ECM, extracellular matrix; MMP, matrix metalloproteinase.

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THE ELASTASE: ANTIELASTASE HYPOTHESIS

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Elastin, the principal component of elastic fibers, is a highly stable component of the extracellular matrix that is critical to the integrity of the lung. The elastase:antielastase hypothesis proposed in the mid-1960s states that the balance of elastin-degrading enzymes and their inhibitors determines the susceptibility of the lung to destruction resulting in air space enlargement. This hypothesis was based on the clinical observation that patients with genetic deficiency in α1 antitrypsin (α1AT), the inhibitor of the serine proteinase neutrophil elastase, were at increased risk of emphysema, and that ...

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