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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
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Introduction |
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 TOP Introduction Collagen vs Elastin in...Repair After InjuryBronchiolitis and Emphysema:...Implications for Specific... |
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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.
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Collagen vs Elastin in Pathogenesis of Emphysema |
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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
1-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
1-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 1-antitrypsin
has neutrophil elastase as its main substrate. For this reason and
because of the pulmonary neutrophilia of 1- 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.
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Repair After Injury |
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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.
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Bronchiolitis and Emphysema: Dual Mechanisms of Airflow Obstruction in COPD |
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Implications for Specific Therapy of COPD |
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TOPIntroductionCollagen vs Elastin in...Repair After InjuryBronchiolitis and Emphysema:...Implications for Specific... |
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1-antitrypsin augmentation therapy in persons with
1-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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W.-D. Kim, W.-S. Kim, Y. Koh, S.-D. Lee, C.-M. Lim, D.-S. Kim, and Y.-J. Cho Abnormal Peripheral Blood T-Lymphocyte Subsets in a Subgroup of Patients With COPD* Chest, August 1, 2002; 122(2): 437 - 444. [Abstract] [Full Text] [PDF]
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