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Clinical Relevance Summary*: Collagen vs Elastin in Pathogenesis of Emphysema; Cellular Origin of Elastases; Bronchiolitis vs Emphysema as a Cause of Airflow Obstruction FREE TO VIEW

Gordon L. Snider, MD, FCCP
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*From the Boston Veterans Affairs Medical Center, Boston, MA.

Correspondence to: Gordon Snider, MD, FCCP, Chief Medical Service 111, Boston VA Medical Center, 150 S. Huntington Ave., Boston, MA 02130

Chest. 2000;117(5_suppl_1):244S-246S. doi:10.1378/chest.117.5_suppl_1.244S
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Abbreviation: CdCl2 = cadmium chloride

In this summary of the clinical significance of the first day’s presentations, I shall focus on three topics. The relative roles of collagen and elastin injury in the pathogenesis of emphysema, the cellular origin of elastases that may play a role in degrading elastin in emphysema, and the relative roles of bronchiolitis vs emphysema in causing airflow obstruction.

The two main forms of emphysema in usual COPD are centrilobular and panacinar emphysema. Centrilobular emphysema begins with inflammation in the terminal and respiratory bronchioles, with subsequent enlargement of the adjacent respiratory airspaces. The resulting microbullae occupy a place in the center of the secondary lung lobule, hence the designation centrilobular emphysema. Airspace enlargement spreads outward from the center of the lobule. Panacinar emphysema arises by simultaneous, uniform destruction of the walls and enlargement of all the respiratory airspaces of the lung acinus. Hence, the designation panacinar. Panacinar emphysema is not associated with bronchiolitis.

The distribution of the two forms of emphysema in the lungs differs. Centrilobular emphysema predominates in the upper lung zones, panacinar emphysema in the lower lung zones. Both types of emphysema are found in COPD; about half the patients have both forms of emphysema and about 25% have largely one form or the other. Sections of centrilobular emphysema show broad bands of fibrosis, whereas centriacinar emphysema fails to show fibrosis. Biochemical studies of dissected lung tissue that is the site of centrilobular emphysema show increased concentration of collagen with normal concentration of elastin when the emphysema is mild; when the centrilobular emphysema is severe, there is a decrease in elastin concentration as well as increase in collagen concentration. Centriacinar emphysema shows a decrease in elastin concentration, with no change in collagen concentration compared to normal. Compliance is normal in lung tissue containing centrilobular emphysema. However, the microbullae of centrilobular emphysema show decreased compliance compared both with the lung that contains them and with normal lungs.

The varying distribution of centrilobular and panacinar emphysema within the lungs, the varying anatomy of the mild lesion, the different association with bronchiolitis, and the differences in collagen and elastin concentration in the two forms of emphysema, strongly supports the hypothesis that their pathogenesis is different.

Additional data for a role of collagen in the pathogenesis of emphysema comes from the studies of Kuhn more than 25 years ago, showing that collagen metabolism as well as elastin metabolism was altered after experimental pancreatic elastase injury of the lungs. Most recently, the studies have been published showing that transgenic mice expressing collagenase (MMP1) developed emphysema, thus implicating both collagen and collagenase in the pathogenesis of emphysema.

Pathogenesis of Centrilobular and Panacinar Emphysema
The Elastase-Antielastase Hypothesis: Panacinar emphysema in virtually pure form is the parenchymal lesion of α1-antitrypsin deficiency. It has been posited for more than 35 years that elastase-antielastase imbalance is the cause of the panacinar emphysema. Briefly, the hypothesis is that elastases of inflammatory cell origin, mainly neutrophils and macrophages, overcome the antielastase defenses of the lungs, degrade elastic and other connective tissues of the lungs, and thereby give rise to emphysema. Among the many pieces of indirect evidence supporting this hypothesis is the increased inflammation in the BAL fluid of nonsmokers with α1-antitrypsin deficiency and the even greater inflammatory response in smokers with this genetic disorder. Also, elastase-induced experimental emphysema is panacinar in type.

It has been known for many years that α1-antitrypsin has neutrophil elastase as its main substrate. For this reason and because of the pulmonary neutrophilia of α1- antitrypsin and of smokers, the neutrophil was thought to be the main source of elastase in the pathogenesis of emphysema. In recent years, the macrophage has also been shown to be the source of a metalloelastase, which is capable of degrading elastin. The macrophage is also the source of this enzyme’s inhibitor, tissue inhibitor of metalloprotease. Recent elegant studies, using a transgenic mouse with deleted metalloprotease gene, showed that this enzyme is essential to the production of emphysema due to cigarette smoking in mice. These studies emphasize the possibility that the macrophage may be as important in the pathogenesis of human emphysema as the neutrophil.

The Inflammation-Fibrosis Hypothesis: The histologic and biochemical prominence of collagen in centrilobular emphysema suggests that some mechanism other than elastase-antielastase imbalance is at work. Because inflammation is prominent in the lungs of smokers with normal serum proteins, it has been suggested that the airspace enlargement of centrilobular emphysema is due to inflammation and fibrosis. Experimental cadmium chloride (CdCl2) injury gives rise to interstitial fibrosis, followed in a few weeks by airspace enlargement. When the CdCl2 is given by inhalation of an aerosol, the interstitial inflammation and subsequent airspace enlargement is centrilobular in distribution; the process is diffuse when the CdCl2 is given by intratracheal instillation. It has been shown in the latter model that neonatal elastin is not decreased in amount during the process of development of airspace enlargement. The mechanism of airspace enlargement is most likely initially due to alveolar epithelial necrosis with collapse of alveoli. Subsequently, organization of intra-alveolar exudate gives rise to newly formed connective tissue and incorporation of alveoli into the interstitium. As collagen undergoes maturation and contraction, local forces give rise to further distention of airspaces.

Because there is a decrease in elastin concentration in severe human centrilobular emphysema, it seems likely that centrilobular emphysema is caused by both inflammation plus fibrosis and elastase-antielastase imbalance. To reiterate, current evidence suggests that panacinar emphysema is due entirely to elastase-antielastase imbalance, whereas centrilobular emphysema is due to a combination of inflammation plus fibrosis and elastase-antielastase imbalance.

The ability to initiate a repair process after injury is an inherent property of all tissues. However, the repair process rarely returns a tissue to its pristine pre-injury state. Desmoplasia is a part of most repair processes and occurs in lung in response to tissue destruction. The ability of the body to repair a tissue is influenced by nutrition, aging, and likely by genetic factors.

Damaged elastic fibers can, like other tissues, undergo repair. Synthetic repair occurs as a result of the de novo production of entirely new elastic fibers after complete destruction of existing elastic fibers. This type of repair is generally accompanied by marked disorganization of lung architecture. If the destructive process is mild, so that elastic fibers lose their integrity but are not ruptured, they are just nicked, and the fibers can be restored to normal by the process of salvage repair. Tropoelastin made by fibroblasts is incorporated into the damaged fiber. Because fiber rupture has not occurred, lung architecture need not be disrupted.

The Balance Between Elastin Degradation and Repair

It seems reasonable to postulate a second balance, in addition to the elastase-antielastase balance in the lungs that is important in the pathogenesis of emphysema. That second balance is the balance between degradation and repair. As long as repair can keep up with elastin degradation, emphysema does not result; if the rate of elastin degradation exceeds the rate of repair, emphysema does result. We do not know the rate of development of emphysema in COPD. In a susceptible smoker for 20 years, emphysema could develop along a linear course from middle to old age. Alternatively, the course of emphysema could be hyperbolic, developing along an accelerating course as advancing years impaired the ability of the lung to repair damaged elastic tissue.

A report about 18 months ago, by the Massaros, that al-trans retinoic acid was able to restore the architecture of pancreatic elastase-induced emphysema in rats to normal, electrified the lung community. Although it seemed almost to good to be true, here for the first time was a treatment that might restore the architecture of emphysematous lung tissue. In reviews presented at this meeting, Paula Belloni clearly reviewed the physiology of retinoic acid in lung growth and repair; and Tepper and colleagues, in a study of lung function in rats with elastase-induced emphysema, showed that airflow obstruction, total lung capacity, and residual volume were partially restored by retinoic acid treatment; compliance, peak expiratory flow, and CO diffusing capacity were not affected. Although mice seem less susceptible to undergoing repair of emphysema with retinoic acid treatment, Belloni reported that the agent does work in at least some experiments. We all look forward with great interest to the human work with retinoic acid that is just beginning.

Airflow obstruction is caused in COPD by two mechanisms. Bronchiolitis, with pathologic changes of inflammation, fibrosis, luminal mucus, and muscle hypertrophy and contraction is one mechanism. This mechanism is partially reversible. The other mechanism is the loss of lung elastic recoil and rupture of alveolar attachments to small, poorly supported airways. In inspiration, these airways are held open. However as lung volume decreases, these airways collapse at a lung volume much above the point of small airway closure in normal persons. Some years ago, I concluded from a review of the literature that, early in the course of COPD, airflow obstruction was due primarily to bronchiolitis. Late in the course of the disease, emphysema assumed much greater prominence. The CT study reported at this meeting by Stanescu and colleagues supports that concept. However, it is clear that a crossectional study of persons with varying degrees of airflow obstruction due to COPD, or preferably, a longitudinal study using CT, will be needed to definitively answer this question.

Because cigarette smoking accounts for 85 to 90% of the risk for developing COPD in the developed world, it follows that prevention of smoking initiation and assisting patients in smoking cessation are the best ways of preventing COPD. There is accumulating evidence that both neutrophils and macrophage elastases are important in the pathogenesis of emphysema. Their relative roles may vary from patient to patient and over time in a single patient. Hence, synthetic inhibitors of neutrophil elastase may have limited benefit in preventing emphysema in persons who cannot stop smoking. Furthermore, α1-antitrypsin augmentation therapy in persons with α1-antitrypsin deficiency may have limited efficacy in preventive therapy.

Retinoic acid or other growth promoting factors may repair panacinar emphysema, but they are unlikely to be able to repair centrilobular emphysema because of its different pathogenesis. Neither is retinoic acid likely to affect bronchiolitis. Physiologic repair of emphysema may be incomplete despite apparently effective anatomic repair. The mix of centrilobular and panacinar emphysema and of bronchiolitis may be critical to determining the response of humans with COPD to retinoic acid treatment. Because airflow obstruction may not be greatly affected, high-resolution CT will be critical as a surrogate for emphysema repair.




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