Cigarette smoking accounts for an estimated 80 to 90 percent of the risk of developing COPD. Age of starting, total pack-years, and current smoking status are predictive of COPD mortality.1 Of note, only 15 percent of smokers develop clinically significant COPD. A variety of other environmental risk factors, such as respiratory infections, occupational exposures, ambient air pollution, passive smoke exposure, and diet, have been suggested, but supporting data is lacking. The only proven genetic risk factor is a1-antitrypsin deficiency. Airway hyperresponsiveness, which may relate to environmental factors, genetic factors, or both, is a potential risk factor that has received significant attention. However, although airway hyperresponsiveness predisposes individuals to decline in pulmonary function and is a defining component in asthma, the relationship of asthma to COPD is unclear.
The earliest objective changes in the evolution of COPD are clinically imperceptible and are measured as small increases in peripheral airway resistance or lung compliance. The slow, insidious appearance of dyspnea and hypersecretion often requires several decades of disease. The sedentary life habits of many cigarette smokers result in failure to unmask exertional dyspnea, and denial results in suppression of symptoms or attribution of such symptoms to aging, poor conditioning, obesity, or allergies. Further, the respiratory consequences of cigarette smoking are a continuum of slowly evolving and latent effects, unique to each individual, in a complex dose-response relationship. Early in disease evolution, abstinence from smoking may eliminate symptoms and result in physiologic improvement. Once well established, however, abnormalities persist and may still progress despite abstinence.
Pathologic specimens from the patients with early disease demonstrate minor metaplasia of bronchial epithelium and an increase in bronchial gland number and size.11 As disease evolves, such findings are exaggerated, acute and chronic inflammatory changes in the epithelium are more notable, and acinar expansion, destruction, and coalescence are seen. Elements of emphysematous disease are invariably present in concert with those of bronchitic disease, though one often predominates.
Despite recognition of causative factors, what determines the clinical onset and rate of progression of chronic airflow obstruction, and the direction toward either emphysematous or bronchitic patterns, is uncertain. Clearly, there is a great deal of variability in disease pattern and severity among individuals with seemingly similar predisposition to disease.
The central element in the pathophysiology of chronic airflow obstruction is impedance to airflow, especially expiratory airflow, due to increased resistance or decreased caliber throughout the small bronchi and bronchioles. Airflow obstruction results from a combination of airway secretions, mucosal edema, bronchospasm, and bronchoconstriction from impaired elastance. Impedance to airflow alone accounts substantially for the abnormal physiology of the disease. Exaggerated airway resistance either reduces total minute ventilation or increases respiratory work. To the degree that alveolar hypoventilation occurs, hypoxemia and hypercarbia result. Even without hypoventilation, hypoxemia occurs due to ventilation-perfusion mismatching.
In addition to obstruction of peripheral airways, all forms of advanced chronic airflow obstruction involve other pathophysiologic elements to complete the overall picture. Particularly in dominantly emphysematous disease, destruction and coalescence of alveolar architecture results in reduction of total "matched" alveolar-capillary surface area for diffusion of gas, while vascular destruction results in "unmatched" regions where ventilation is wasted.
Neurochemical and proprioceptive ventilatory responses in chronic airflow obstruction may be aberrant. For example, ventilatory response to hypercarbia may be blunted during sleep, and ventilatory drive and dyspnea may be exaggerated in spite of normal pulmonary inflation. The composition of muscle fiber types, breathing patterns, and resistance to fatigue of respiratory muscles are also altered in advanced chronic airflow obstruction. Finally, pulmonary arterial hypertension supervenes as chronic airflow obstruction progresses. The right ventricle transiently hypertrophies, and then dilates with the evolution of overt cor pulmonale. A low-output state in the pulmonary circulation translates into low left ventricular output. Arterial hypoxemia increases as the effects of right-to-left shunt on poorly oxygenated mixed venous blood are exaggerated. Right ventricular pressure overload is clinically poorly tolerated and associated with atrial and ventricular arrhythmias.
Even though COPD is becoming increasingly recognized as a chronic inflammatory disease of the lower airways, the role of inflammation in its pathogenesis remains a matter of debate. In current COPD guidelines, there is no mention of lower airway inflammation in the definition of COPD. 1,6,7,8,,9 and 1°
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