Role of Mechanical Forces in the Progession of Emphysema

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DESCRIPTION (Applicant's abstract): It is generally accepted that emphysema develops through an imbalance of protease and anti-protease activity in the lung, resulting in enzymatic destruction of elastin fibers within the alveolar wall. However, preliminary data from our laboratory demonstrate the emphysema can be induced in ways that do not involve elastin. We have observed that collagen fibers in the lung tissue of rats treated only with elastase can rupture under the mechanical forces that are required for normal breathing. Since collagen is much stronger than elastin, and protects the alveoli from rupture at high distending pressures, even if elastin is damaged, the alveolar wall can not possibly rupture unless collagen is weakened, and thus prone to mechanical failure. This observation has led us to formulate two hypotheses: 1) Following the onset initial progression of emphysema due to proteolytic injury, a critical point is reached at which the mechanical forces required to maintain normal breathing are sufficient to gradually damage and rupture the remodeled alveolar walls; 2) A key element of emphysema is extracellular repair and the common link among the various animal models of emphysema is the generation of remodeled weak collagen fibers that can rupture under mechanical forces. To test these hypotheses we will determine whether mechanical forces can rupture the alveolar walls in three acute injury murine models (elastase, collagenase and proteoglycan digestion treatments) of emphysema, and "knock out" and transgenic murine models of spontaneous emphysema. Measures of remodeling and inflammation will be correlated with lung function at 2 time points during the progression of emphysema. Physiological measurements, biochemical and molecular biology studies as well as simultaneously mechanical failure testing and microstructural imaging will be utilized to: 1) assess whether collagen remodeling is a critical common feature in the pathophysiology of all types of emphysema; 2) determine the structural basis for collagen failure; and 3) assess whether the relentless progression of emphysema that is observed clinically is due to self-propagating failure that occurs during the process of normal breathing.