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Fallingwater is falling down because Frank Lloyd Wright ignored the advice of an engineer and used beams too weak to bear the house's weight (1). The study by Kononov and colleagues (2) appearing in this issue (pp. 1920-1926), illustrates a similar causal factor in the pathogenesis of emphysema that lay dusty and forgotten for decades. This study deals specifically with elastase-induced emphysema in rats. Many of the findings are probably unique to that animal model. However, their implications have relevance to normal aging, smoker's emphysema, lung volume reduction surgery (LVRS), exacerbations of chronic obstructive pulmonary disease (COPD), and possibly even pulmonary rehabilitation.
Kononov and colleagues studied lung slices from control rats and rats pretreated with intratracheal elastase. They show that the stress-strain relations of the lung slices in vitro mirror the pressure-volume relations of the whole lungs. By immunohistochemical staining for elastin and collagen, they also elegantly demonstrate the remodeling of both of these structural elements after elastase. Finally, they provide vivid evidence of the damaged elastin and collagen rending under stresses approximating those of tidal breathing. This study shows the interaction between the microscopic structure and macroscopic stress in the lung with unique clarity across multiple scales.
Since the first descriptions of patients with 
1 antitrypsin deficiency, the pathogenesis of emphysema has been attributed to an
imbalance between proteinases and antiproteinases. The family of known proteinases and their inhibitors continues to grow, and we are beginning to understand their interactions with inflammatory cells, tobacco smoke, pollutants, and oxidant stress. However, the focus upon enzymatic digestion of the lung conveys an
image of it slowly dissolving away, alveoli coalescing into cysts
like soap bubbles in foam. This image overlooks something obvious. The lung is an organ under stress, stretched daily with 15,000 inspirations, yawns, sighs, and coughs. Stress fatigue and failure of weakened structural elements is the other side of the image illuminated by Kononov and colleagues.
The importance of mechanical forces in emphysema pathogenesis has not always been so ignored. Early animal models of the disease produced emphysema-like changes by extensive lung resection, increasing stress on the remaining lung (3), or by inducing severe hyperinflation with valves placed in central airways (4). Phrenectomy was attempted for emphysema to prevent hyperinflation. West attributed the upper-lobe predominance of typical smoker's emphysema to the greater stress in nondependent alveolar septae (5).
The normal lung is remarkably capable of withstanding a lifetime of repetitive stress. Normal lung tissue is resilient. Moreover, living tissue, unlike trusses or beams, is capable of self-repair. Despite this, aging lungs of nonsmokers show emphysematous changes, including histologic features, increases in mean alveolar size, and decreased lung recoil (6, 7).
In the emphysematous lung, elastin and collagen are fragmented and structurally unsound. It is logical that these supporting elements would be more prone to fail under the daily stress of tidal breathing. Whereas apnea is an unappealing approach to preserving FEV1, it is intriguing to speculate how hyperpnea might contribute to disease progression. Emphysema perversely increases the stress on the lung even as it weakens the structure. Patients with emphysema have an increased resting respiratory rate. Many have daily cough, each one preceded by a deep inspiration. With exertion, they hyperinflate such that each breath ends near TLC. Regular exercise, despite well-documented benefits for patients with emphysema, could likewise contribute to its long-term progression. In papain-induced emphysema in rats, daily running reduced the saline-filled lung static recoil pressure compared with that of rested, emphysematous animals (8). The decline in lung function in some smokers with COPD is punctuated by acute exacerbations from which the patient never fully recovers (9). COPD exacerbations typically increase total ventilation and worsen hyperinflation. This might accelerate the failure of elastic elements in vulnerable patients.
In patients undergoing LVRS, elastic recoil of the remaining lung is increased. Long-term follow-up of these patients shows that benefits of surgery are lost at a highly variable rate. However, the reported mean declines in FEV1 greatly exceed what has been reported in nonsmoking patients with COPD (10). Loss of function occurs in association with loss of lung recoil within a year after LVRS (11). Patients who achieve the greatest initial improvement in FEV1 also show the most rapid decline (12). These findings suggest that the increased stress on the lung tissue is causing the accelerated loss of function.
Like the emphysematous lung, there are a few elements of the study by Kononov that develop holes under stress. The investigators claim that the biomechanical characteristics of the lung slices are unaltered by their fixation and immunohistochemical staining. They also show that the range of linear stress approximates that of normal tidal breathing. However, they readily observe alveolar wall fracture and sometimes complete rupture of the lung strips with a single cycle of stretch. If their assertions are correct, then it is fortunate they killed these rats when they did, because they would have died within another breath or two. The remodeling of collagen fiber structure observed after elastase treatment is interesting. However, given the many differences between this model of emphysema and the human version, it may be more relevant to the model than to the disease. Finally, longitudinal stretch applies different forces than does inflation of the lung. For example, the angles between adjacent alveolar walls are changed when a lung strip is stretched, but not when a lung is inflated.
Nevertheless, the contribution of this report is not only in its new data, but also in how it reminds us of the old data. Emphysema is not just the result of an imbalance between proteinases and antiproteinases. It also requires an imbalance between the tensile strength of the lung and the stress of ventilation. Detailed knowledge of cement is not a comprehensive understanding of architecture. Expertise in proteolysis will not provide a comprehensive understanding of emphysema. Truly understanding the architecture of the lung and how it fails in emphysema will require the sort of integrative approach exemplified by this study by Kononov and colleagues.
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References |
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1. New York Times, September 23, 2001.
2.
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Brewer K,
Sakai H,
Cavalcante FSA,
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Ingenito EP,
Suki B.
Roles of mechanical forces and collagen failure in
the development of elastase-induced emphysema.
Am J Respir Crit
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1920-1926
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Adams WE,
Livingstone HM.
Lobectomy and pneumectomy in dogs.
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4. Harris WH, Chillingworth FP. The experimental production in dogs of emphysema with associated asthmatic syndrome by means of an intratracheal ball valve. J Exp Med 1919; 30: 75-85 [Abstract].
5. West JB. Distribution of mechanical stress in the lung, a possible factor in localization of pulmonary disease. Lancet 1971; i: 839-841 .
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Airspace size in lungs of lifelong non-smokers: effect of age and sex.
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Elasticity of human lungs in relation to
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Exercise stress and enzyme-induced emphysema.
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Gelb AF,
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Lung function 12 months following emphysema resection.
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Brenner M,
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