Pathogenesis

The term COPD refers to the clinical and physiological consequences of an amalgam of chronic respiratory diseases that nearly always includes varying degrees of emphysema and chronic obstructive bronchitis. Because airway hyperreactivity commonly accompanies COPD, asthma or asthmatic bronchitis may also contribute to the evolving pathological features. The generic definition of COPD includes the late sequelae of cystic fibrosis, diffuse bronchiectasis, rheumatoid bronchiolitis, and other unusual diseases. But the great majority of patients with COPD–those who are the subject of this book–are tobacco smokers who appear to differ from other smokers in their unusual susceptibility to tobacco smoke.

The mechanisms that underlie this susceptibility are largely unknown. Only one factor, alpha-1-antitrypsin deficiency, has been clearly identified, but it accounts for only a small fraction of all COPD cases. Exposure to environmental or occupational dusts and gases may also lead to COPD, and this exposure is believed to cause many cases not attributable to tobacco smoke, especially in developing countries. This discussion of the pathogenesis of COPD therefore includes a description of alpha-1-antitrypsin deficiency, the mechanisms by which tobacco smoke and other inhaled pollutants may cause emphysema and chronic obstructive bronchitis, and how these diseases culminate in chronic airflow obstruction. The pathogenic pathways for these conditions are not well understood, but they are probably linked to chronic inflammation of the lung parenchyma and airways.

Alpha-1-Antitrypsin Deficiency

An important discovery was announced in 1963 by Laurell and Eriksson, who reported that persons with a hereditary deficiency of alpha-1-antitrypsin, (AAT), a powerful protease enzyme inhibitor, developed panlobular emphysema at a much earlier age than those with ordinary COPD. The circulating level of alpha-1-antitrypsin is genetically determined by a single gene on single gene on chromosome 14, and the serum protease inhibitor phenotype (Pi type) is governed by independent expression of the two parental alleles. Further investigation disclosed that nearly all (95%), of those persons afflicted with aat deficiency are homozygous for the Z allele, and thus are designated Pi ZZ. Most healthy persons with normal levels of alpha-1-anti-trypsin have M alleles and are designated Pi MM. Pi MZ persons have serum levels of alpha-1-antitrypsin that are intermediate between Pi MM and Pi ZZ phenotypes, but heterozygotes are not at increased risk for emphysema. Many other phenotypes have been described, but most are not associated with emphysema.

Alpha-1-antitrypsin can inhibit the activity of several proteolytic enzymes, particularly neutrophil elastase. It plays a key role in preventing tissue destruction from excessive proteolysis during inflammatory reactions. Most persons have sufficient alpha-1-antitrypsin in their lungs and bloodstream to protect the lungs from proteolytic enzyme-induced damage during inflam-mation caused by tobacco smoke, other inhaled toxins, or infections. In contrast, patients with Pi ZZ pheno-types who lack alpha-1-antitrypsin are unable to control these inflammatory reactions, and emphysema develops after unrestrained proteolysis has damaged the elastic fiber network and the extracellular matrix of the lungs.

Emphysema

The discovery that patients with extremely low levels of serum alpha-1-antitrypsin had clinical emphysema, coupled with the experimental observation that papain, a plant enzyme with elastinolytic properties, could induce emphysema when instilled into the lungs of laboratory animals, led to the elastase-antielastase hypothesis of the pathogenesis of emphysema. In its simplest form, the elastase-antielastase theory avers that the net balance between the elastinolytic activities unleashed by the neutrophilic component of inflammation and the antielastinolytic defenses of the lungs determines whether or not emphysema will develop. The balance is clearly tipped in favor of neutrophil elastase-induced damage in patients with Pi ZZ alpha-1-antitrypsin deficiency. Conceivably, the balance could be tipped in the same direction in tobacco smokers in whom exuberant inflammatory reactions release abundant neutrophil elastase and overwhelm normal antielastinolytic defenses. This argument was strengthened by the observation that activated neutrophils also release potent free radicals of oxygen that are capable of inactivating alpha-1-antitrypsin through oxidation, even when aat is present in normal amounts, thereby allowing unimpeded action of neutrophil elastase.

But this hypothesis, which was enthusiastically greeted some 30 years ago, is now considered a naive oversimplification of the complex processes at work. Clearly, other cells besides neutrophils, particularly macrophages and possibly mesenchymal cells, contribute to the development of emphysema. Also, many other enzymes besides neutrophil elastase (such as cathepsins G, B, L, and D, collagenase, gelatinase, and proteinase-3) participate in the destructive process. The concept is emerging that smoking and many other kinds of inflammatory injuries yield a cocktail of proteinases that destroy lung tissue in a coordinated action that culminates in emphysema. Thus, emphysema has been viewed as the lungs’ stereotyped response to a variety of injurious insults.

Even if we accept this revised hypothesis, a fundamental question still remains: Why are only a small fraction of smokers (perhaps 15% to 20%) susceptible to the development of progressive airflow obstruction with emphysema? This profound question of “host variation” suggests that other unknown and important factors, either inherited or acquired, affect pathogenesis.

Chronic Obstructive Bronchitis

As stated, pulmonary emphysema nearly always coexists with some degree of chronic obstructive bronchitis with inflammation of both large and small airways. However, there are even more problems with chronic bronchitis than with emphysema in identifying the responsible pathogenic mechanisms, because neither the symptoms that define the syndrome of chronic bronchitis (chronic cough and sputum production) nor the pathological findings (inflammation and hyperplasia of the secretory structures) are specific for the disorder.

The kind of chronic obstructive bronchitis that we are concerned about is presumed to result from injury to the peripheral airways by tobacco smoke or environmental or occupational dusts and gases. These toxins undoubtedly behave like other injurious agents in that the severity of the resulting damage depends on the concentration of the inhalant and the duration of exposure. Thus, heavy and prolonged exposure, usually to cigarette smoke, is nearly always identifiable in patients with COPD.

Although the pathogenesis of tobacco-induced chronic bronchitis is incompletely understood, we do know that the repeated inhalation of tobacco smoke causes hyperplasia of mucous glands in the bronchi and an increase in the number and proportion of secretory cells in bronchioles, where a neutrophilic and mononuclear cell inflammatory reaction also occurs. Finding elastase in the sputum of patients with chronic bronchitis supports the suggestion that the antiproteolytic defenses are overwhelmed in this disorder, and that a proteolytic cascade, not unlike that which leads to emphysema, injures small airways and contributes to their narrowing. Nevertheless, it is again necessary to evoke “host factors” to account for differences in damage among smokers from what appears to be quantitatively similar exposure. We have almost no understanding about why some persons with chronic bronchitis relent lessly progress to severe airflow obstruction, while many others remain relatively stable despite the fact that they continue to smoke.

Chronic Airflow Obstruction

Twenty years ago it was thought that expiratory airflow obstruction could occur in only two ways: narrowing of airways, which was equated with chronic bronchitis, and loss of elastic recoil, which was associated with emphysema. Now, as recently emphasized by Thurlbeck, it is more reasonable to consider that tobacco smoke has a generalized injurious effect on the lungs and airways, and that expiratory airflow limitation is the consequence of multiple processes that may occur separately, but usually occur together in various combinations.

One injury leads to chronic bronchitis, one of the early effects of smoking on the central airways that has little effect on airflow. Another abnormality is bronchiolar inflammation, which narrows and deforms peripheral airways and is an important cause of airflow obstruction. A third is inflammation of the parenchyma, which causes emphysema and airflow obstruction by decreasing elastic recoil through damage to the lungs’ connective tissue matrix. Finally, smoking-induced parenchymal inflammation and breakdown result when the attachments between alveolar walls and neighboring bronchioles are destroyed, allowing the airways to narrow because of a loss of tethering.

References

Laurell CB, Eriksson S. The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. Scand J Lab Clin Med 1963;15:132-140. The original report on the association between alpha-1-antitrypsin and emphysema; still worth reading.

Snider GL, Faling LJ, Rennard SI. Chronic bronchitis and emphysema. in Murray JF, Nadel JA (eds), Textbook of Respiratory Medicine, 2nd ed. Philadelphia: WB Saunders, 1994, pp 1331-1397. An excellent comprehensive summary of the pathogenesis, diagnosis, and treatment of COPD.

Tetley TD. New perspectives on basic mechanisms in lung disease. 6. Protease imbalance: Its role in lung disease. Thorax 1993;48:560-565. A recent review of the elastase-antielastase hypothesis that stresses the multiplicity and complexity of the factors involved.

Thurlbeck WM. Emphysema then and now. Can Respir J 1994;1:21-39. The newest and best review of the pathology and pathologic-radiographic-clinical correlations of COPD.