Pathogenesis of Emphysema PDF

## Pathogenesis of Emphysema **Smoking or air pollutant** + **Genetic predisposition** **Congenital a1-antitrypsin deficiency** **Oxidative stress, increased apoptosis and senescence** **Inflammatory cells, release of inflammatory mediators** **Protease-antiprotease imbalance** **Alveolar wall des...

## Pathogenesis of Emphysema **Smoking or air pollutant** + **Genetic predisposition** **Congenital a1-antitrypsin deficiency** **Oxidative stress, increased apoptosis and senescence** **Inflammatory cells, release of inflammatory mediators** **Protease-antiprotease imbalance** **Alveolar wall destruction** **FIG. 11.6 Pathogenesis of emphysema. See text for details.** With a genetic predisposition, result in parenchymal destruction. Factors that influence the development of emphysema include the following (Fig. 11.6): ### Inflammatory Cells and Mediators - A wide variety of inflammatory mediators have been implicated (including leukotriene B4, the chemokine IL-8, the cytokine tumor necrosis factor [TNF], and others). - These serve to recruit additional inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors). - The inflammatory cells present in lesions include neutrophils, macrophages, and CD4+ and CD8+ T cells. It is not known what antigens the T cells are specific for. ### Protease-Antiprotease Imbalance - Several proteases are released from the inflammatory cells and epithelial cells that break down connective tissues. - In patients who develop emphysema, there is a relative deficiency of protective antiproteases (discussed below). ### Oxidative Stress - Reactive oxygen species are present in cigarette smoke, which also contains particles and other substances that stimulate the release of additional reactive oxygen species from inflammatory cells such as macrophages and neutrophils. - These cause tissue damage and inflammation (Chapter 2). ### Airway Infection - Although infection is not thought to play a role in the initiation of tissue destruction, bacterial and/or viral infections cause acute exacerbations. The idea that proteases are important is based in part on the observation that an inherited deficiency of the antiprotease al-antitrypsin predisposes to emphysema, an effect that is compounded by smoking. - About 1% of patients with emphysema have this defect. - al-antitrypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation. - It is encoded by the proteinase inhibitor (Pi) locus on chromosome 14. - The Pi locus is polymorphic, and approximately 0.01% of the US population is homozygous for the Z allele, a genotype that is associated with markedly decreased serum levels of al-antitrypsin. - More than 80% of these individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes. **Protease-mediated damage of extracellular matrix has a central role in the airway obstruction seen in emphysema.** - Small airways are normally held open by the elastic recoil of the lung parenchyma, and the loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory (WHO) as "a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities caused by exposure to noxious particles or gases." - COPD affects more than 10% of the US adult population over the age of 40 years. - It is the fourth leading cause of death in this country, the third leading cause of death worldwide, and is rising in frequency due to increases in cigarette smoking in parts of Africa and Asia. - Overall, 35% to 50% of heavy smokers develop COPD; conversely, about 80% of COPD is attributable to smoking. - Women appear to be more susceptible than men to developing COPD. - Additional risk factors include poor lung development early in life, exposure to environmental and occupational pollutants, airway hyperresponsiveness, and certain genetic polymorphisms. Although emphysema and chronic bronchitis often occur together as part of COPD, it is useful to discuss these patterns of lung injury and associated functional abnormalities individually to highlight the pathophysiologic basis of different causes of airflow obstruction (Fig. 11.4). We will conclude our discussion by returning to the clinical features of COPD. ## Emphysema **Emphysema is characterized by permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls but without significant fibrosis.** - It is classified according to its anatomic distribution. - As discussed earlier, the acinus is the structure distal to terminal bronchioles, and a cluster of three to five acini is called a lobule (Fig. 11.5A). - There are four patterns of emphysema: 1. centriacinar, 2. panacinar, 3. distal acinar, and 4. irregular. - Only the first two types are associated with COPD, with centriacinar emphysema being about 20 times more common than panacinar disease. ### Centriacinar (Centrilobular) Emphysema - The distinctive feature of centriacinar emphysema is involvement of the central or proximal parts of the acini with sparing of the distal alveoli. - Thus, both emphysematous and normal air spaces exist within the same acinus and lobule (Fig. 11.5B). - The lesions are more common and severe in the upper lobes, particularly in the apical segments. - In advanced centriacinar emphysema the distal acinus is also involved, making it difficult to differentiate from panacinar emphysema. - Centroacinar emphysema is most common in individuals who smoke cigarettes, in whom it is often accompanied by chronic bronchitis. ### Panacinar (Panlobular) Emphysema - In panacinar emphysema, the acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli (Fig. 11.5C). - In contrast to centriacinar emphysema, panacinar emphysema occurs more commonly in the lower lung zones and is associated with al-antitrypsin deficiency. ### Distal Acinar (Paraseptal) Emphysema - In this form of emphysema, the part of the acinus distal to the respiratory bronchiole is primarily affected. - It tends to be found near the pleura, along the lobular connective tissue septa, and at the margins of the lobules adjacent to areas of fibrosis, scarring, or atelectasis, and is usually more severe in the upper half of the lungs. - The characteristic finding is multiple enlarged air spaces ranging in diameter from less than 0.5 mm to more than 2.0 cm, sometimes forming cystic structures, that with further enlargement give rise to bullae. - The cause is unknown; it comes to attention most often in young adults who present with spontaneous pneumothorax. ### Irregular Emphysema - Irregular emphysema, so named because the acinus is irregularly involved, is almost invariably associated with scarring. - In most cases it occurs in small foci and is clinically insignificant. ## Pathogenesis Inhaled cigarette smoke and other noxious particles cause lung damage and inflammation which, particularly in notionte