Nicola A. Hanania, M.D., M.S.; Gulshan Sharma, M.D., M.P.H.; Amir Sharafkhaneh, M.D., Ph.D.

Disclosures

Semin Respir Crit Care Med. 2010;31(5):596-606. 

In This Article

Pathophysiological Considerations

Physiological Changes and COPD in the Elderly

Aging affects the structure, function, and control of the respiratory system. Both lungs and chest wall, including the respiratory muscles, undergo changes that can affect respiratory function.[9–11] The elastic recoil of the lungs is the major determinant of maximal expiratory flow and is diminished with aging, causing increased lung compliance at high lung volumes.[9–11] Bronchiolar diameters diminish and alveolar ducts enlarge as a result of the change in lung matrix and elastic properties of lungs. These changes result in decreased expiratory flow and decreased surface area for gas exchange, respectively. Airways in dependent portions of the lung close at higher volumes with advancing age, so that more airways are closed during all or part of the respiratory cycle. The lower portions of the lung are better perfused at all ages, but higher closing volume with age increases ventilation perfusion mismatch and accounts for the declining Pao2 (oxygen pressure) with age. In contrast to the lungs, the chest wall stiffens with age and compliance decreases.[12] Costochondral cartilages become calcified, and intercostal muscle contraction accounts for less chest expansion. Furthermore, changes in the lung and chest wall compliance cause a decline in static and dynamic compliances of the total respiratory system. And this, in turn, increases the work of breathing. In addition, respiratory muscle strength and endurance diminish with age, especially above the age of 55 years.[13] The anterior-posterior diameter of the thorax and the kyphosis of the thoracic spine also increase with age. Changes in skeletal muscle and the thoracic wall may affect clearing of the airway in states where airway mucus hypersecretion occurs, such as in COPD. In addition, cough becomes less vigorous with aging, and, because of the greater closing volume, cough may inadequately clear certain portions of the lungs. Additionally, mucociliary clearance becomes slower and less effective.[14]

Pulmonary functional reserve declines in elderly patients.[9] In nonsmoking men, forced vital capacity (FVC) decreases between 0.15 and 0.3 L/decade, and the forced expiratory volume in 1 second (FEV1) decreases by 0.2 to 0.3 L/decade. These changes are smaller and more gradual in women. Although total lung capacity (proportional to height) does not change significantly with age, residual volume (RV) increases as a consequence of higher closing volume. Control of ventilation is modestly compromised, with blunted responses to hypoxemia, hypercapnia, and mechanical loading. Table 1 summarizes the changes in various respiratory function parameters associated with aging.[12]

Immunopathologic Changes and COPD in the Elderly

The pathology of COPD is complex and includes airway and lung inflammation, airway narrowing and remodeling, and parenchymal lung destruction. In addition, there is now enough evidence to suggest that this disease may be associated with systemic inflammation, which may explain the cardiac comorbidity, cachexia, and muscle weakness that are seen in many patients. The age-associated increase in the prevalence of COPD[5,15,16] suggests that changes related to aging may contribute to COPD pathogenesis.[17,18] The association between COPD and aging is relevant and important because, by 2050, ~22% of the U.S. population will be over 60 years of age,[3] and this increase will almost certainly bring about a concomitant epidemic of chronic diseases such as COPD.

Physiological changes in COPD are responsible for the progressive impairment in exercise tolerance commonly seen in patients suffering from this disease. However, many of the anatomical and physiological changes seen in COPD have also been described in the aging lungs of nonsmokers, suggesting that the aging process may be a contributing factor (Fig. 1). "Senile emphysema" is characterized by airspace dilatation resulting from loss of supporting tissue without alveolar wall destruction and has been described in elderly individuals without COPD. Furthermore, aging is thought to be a proinflammatory condition associated with a dysregulated immune system. Because exaggerated systemic and tissue inflammation is important in COPD pathogenesis, immunologic changes seen in COPD may overlap with those described with advancing age. This has led some to label COPD as an "accelerated aging phenotype" triggered by noxious stimuli like cigarette smoke.[19]

Figure 1.

Smoking and aging-related changes in physiological, anatomical, and immunological parameters. From Sharma et al.19 Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society.

Dysregulation of the innate and adaptive immune systems has been described in COPD pathogenesis as well as in age-associated immunosenescence. Aging and COPD are characterized by increases in proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, which are implicated in aging-related inflammatory diseases and correlated with degree of obstruction in COPD (Table 2). An age-dependent decline in naïve T cells with oligoclonal expansion of CD8+ CD28null T cells from chronic antigenic stimulation has been described.[20] The increase in CD8+ CD28null T regulatory cells inhibits antigen-specific CD4+ T cell responses, leading to a decline in adaptive immune response. A paradoxical upregulation of innate immune system to compensate for the decline in the adaptive immune function may occur and lead to a proinflammatory state. The dysregulated adaptive immune system with activated innate immune responses seen with advanced age promotes recruitment and retention of neutrophils, macrophages, and CD4+ and CD8+ T cells in the lungs of smokers with COPD. Exposure to noxious inhalants such as cigarette smoke, which induces proinflammatory responses and in turn recruits inflammatory cells, constitutes an initiating event in the inflammatory response. Once the inflammation is triggered, a self-perpetuating cascade of inflammation and lung parenchymal damage occurs and persists. Dysregulated immune and inflammatory responses mediate all stages of COPD, from initiation to permanent lung damage, suggesting that COPD is an autoimmune disease.[21–23] Interestingly, COPD in nonsmokers may be associated with organ-specific autoimmunity.

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