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COPD in 2001 : a major challenge for medicine, the

COPD in 2001 : a major challenge for medicine, the COPD is currently the sixth leading cause of death and the 12th leading cause of morbidity

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COPD in 2001 : a major challenge for medicine, the pharmaceutical industry, and society - chronic obstructive pulmonary disease

COPD in 2001 : a major challenge for medicine, the pharmaceutical industry, and society - chronic obstructive pulmonary diseaseCOPD is currently the sixth leading cause of death and the 12th leading cause of morbidity worldwide. (1) Among the leading causes of death and disability, COPD is the one that is rising the most rapidly. By the year 2020, COPD is expected to be the third leading cause of death and the fifth leading cause of disability. (2) Cigarette smoking is the most important cause of COPD, and the current epidemic is in large part due to smoking behavior over the last several decades.

Although smoking cessation reduces the accelerated loss of lung function that is associated with smoking/lung function unfortunately continues to decline in former smokers. As a result, many ex-smokers, who are not currently symptomatic, will develop symptoms of COPD as a loss of pulmonary function associated with aging, which further compromises lungs that have been damaged previously by smoking. As a result, the COPD epidemic will continue for the next several decades, even if major advances are made in controlling tobacco use. (2)

Current treatments for COPD can be extremely helpful in improving symptoms and the quality of life for affected individuals. (4) Patients with COPD, however, restrict their activities in order to avoid sensations of dyspnea, and the disease remains undiagnosed in many patients. A diagnosis of COPD can be made relatively easily using simple physiologic measures such as spirometry. There is, therefore, a significant need for the implementation of the proper diagnosis and management of COPD patients.

Current therapies, however, are limited in important ways. The most effective drugs that are available currently, the bronchodilators that were developed originally for the treatment of asthma, exploit the small degrees of smooth muscle tone that are present in COPD patients. By inducing smooth muscle relaxation, airflow can be improved, but only very modestly. These small gains, perhaps surprisingly, can be exceedingly meaningful for some COPD patients. Dyspnea can decrease, exercise tolerance can improve, and a clinically meaningful and statistically significant improvement in health status, sometimes termed quality of life, may result. While current therapies can clearly be beneficial in treating the symptoms of COPD, new treatments are desperately needed. In particular, the development of novel drugs that ameliorate the inflammatory and abnormal airways secretory responses initiated in response to chronic irritation from inhaled tobacco smoke may provide useful steps toward reduction of the ongoing destruction of the lung parenchyma and the progressive, relentless deterioration in pulmonary function that culminates in respiratory failure and death, which comprise the "holy grail" of therapy in patients with COPD.


An international symposium, which was sponsored by AstraZeneca in Lund, Sweden, in April 2001, and which is documented in this supplement, was instigated to explore and discuss COPD with the intent of highlighting the new understanding of the basic biology underlying this complex syndrome. An increased understanding of the mechanistic bases of COPD has identified a number of potential novel therapeutic targets in this disorder. This understanding, moreover, has underscored the need for novel means with which to assess COPD patients both clinically and for the purposes of evaluating new mechanism-based treatments.

Since the 1960s, the roles of inflammatory cells and the mediators derived from those cells have played an important role in models designed to explain the pathogenesis of COPD. Excessive proteolytic activity of neutrophil elastase in excess of endogenous antielastase protection, the so-called protease/antiprotease model, has long been prominent among these. (5) This model, however, has now been extended to include a variety of other serine and metalloproteases as well as other mediators released by inflammatory cells, including reactive oxidants and cytokines. (6) Moreover, it is now recognized that inflammatory cells, in addition to neutrophils, likely also contribute in important ways to the pathogenesis of COPD. The symposium included discussions of the potential roles of macrophages and lymphocytes, particularly because these cells may be key in determining why the inflammation induced by toxic exposures like cigarette smoke leads to the development of COPD in some individuals but not in others.

A number of features may account for varied individual susceptibility. Genetic factors clearly play a role, although only one specific gene related to COPD, [[alpha].sub.1]-protease inhibitor (also known as [[alpha].sub.1]-antitrypsin) deficiency, has been identified to date. (7) Thus, individuals who are homozygous for [[alpha].sub.1]-antitrypsin deficiency have increased susceptibility for developing pulmonary emphysema, especially if they also smoke. It is also possible, however, that susceptibility can be related to acquired features. Viral infections, for example, can lead to the chronic expression of viral genes that can greatly modulate subsequent inflammatory responses. Inflammatory responses can, moreover, be associated with the development of autoimmunity, which also can modulate subsequent inflammatory processes. Both of these topics were specifically addressed in the symposium.

It is also becoming increasingly clear that the pathogenetic processes initiated in COPD can have multiple effects on target tissues. Airflow limitation likely develops from several processes causing a variety of distinct lesions. (6) These include peribronchiolar fibrosis and narrowing of, as well as destruction of, alveolar walls with loss of lung elastic recoil. COPD also is characterized by alterations of the airways epithelial surface, by phenotypic, proinflammatory changes in epithelial cells, and by altered production of airway secretions and mucus. These latter changes likely lead to both chronic cough and mucus hypersecretion as well as to a predisposition toward developing airway infections. The latter often are associated with exacerbations of COPD that are characterized by acutely increased dyspnea, cough, and secretions. These exacerbations are, moreover, associated with systemic inflammatory responses, which may have adverse systemic effects and may contribute to worsened health status. The symposium included sessions on abnormal epithelial functions, airway secretions, and exacerbations of COPD.

The pathogenetic processes in COPD also can lead to adverse systemic effects. These effects may account for abnormal skeletal muscle function and total body wasting, which characterize COPD. These latter are not directly related to airflow and, therefore, are not directly assessed by measures such as spirometry. Alternate means to assess these key features of COPD are needed both in order to understand the disease process and to develop therapies targeted at the systemic components of the disorder.

A number of novel therapies are under consideration for patients with COPD. In this regard, agents that target specific aspects of the inflammatory response or that target the production and regulation of airway secretions are appealing. Agents that modulate lung repair following injury, moreover, have the potential for restoring lost lung function.

The symposium, which is summarized in the accompanying articles, addressed many of these issues and served to confirm the enormous complexity of the disorder that is COPD. COPD is characterized by embarrassing and distressful symptoms such as persistent cough, excessive sputum production, and dyspnea. Furthermore, this syndrome is associated with slowly progressive, irreversible declines in lung function, repeated pulmonary infections, and muscle weakness. These chronic manifestations of COPD are accompanied by breathlessness, often with only mild exertion, decreased mobility, repeated hospitalizations, reduced quality of life, and ultimately, due to unrelenting respiratory failure, death. Since COPD is usually a result of long-term smoking, patients often have comorbidity associated not only with their habit, but also with aging, including pulmonary hypertension, coronary vascular disease, and cancer.