Again, these observations are not limited to the elastase model, because the tight-skin and pallid mice also showed similar increases in heterogeneities (32). (P< 0.001), and the difference in parameters decreased with increasing positive end-expiratory pressure. The heterogeneity of airspace structure gradually increased over time. Conversely, the relative amounts of elastin and type I collagen exhibited a peak (P< 0.01) at Day 2, but returned to baseline levels by Day 21. Structurefunction relations manifested themselves in strong correlations between compliance parameters and both mean size and heterogeneity of airspace structure (r2> 0.9). Similar relations were also obtained in a network model of the parenchyma in which destruction was based on the notion that mechanical forces contribute to alveolar wall rupture. We conclude that, in a mouse model of emphysema, progressive decline in lung function is sensitive to the development of airspace heterogeneity governed by local, mechanical, force-induced failure of remodeled collagen. Keywords:lung compliance, morphology, elastin, collagen, network model == Clinical Relevance == Both the separate structural and functional properties of the emphysematous lung have been well studied. However, the relation between them is not well understood. Functional properties MK-0679 (Verlukast) of the emphysematous lung are most sensitive to the presence of structural heterogeneity that increases during progression due to the interaction between enzymatic degradation and mechanical forces. Emphysema is characterized by air space enlargement, accompanied by destruction of parenchymal structure (1), and, being a component of chronic obstructive pulmonary disease (COPD), is a major cause of chronic morbidity and mortality worldwide (2). MK-0679 (Verlukast) Although lung transplantation and lung volume reduction are possible therapies, there is no cure for patients with end-stage emphysema (3). The most accepted hypothesis of the pathogenesis of emphysema is an PIK3R1 imbalance between elastase and antielastase activity (4) extended to include other proteases (5). Peripheral airway inflammation (6), oxidative stress (7), and apoptosis (8) are also thought to be involved in the pathogenesis. Some of these mechanisms may interact, leading to remodeling of the extracellular matrix (ECM) (9). While the exact mechanisms of pathogenesis are not fully understood, it is even less clear how the disease progresses. In clinical practice, emphysema progression is characterized by a decline in lung function (10), directly affecting quality of life, or an increase in low attenuation area on lung computed tomography images, indicating tissue destruction (11). However, there is little correlation between indexes derived from computed tomography images and spirometric lung function (11,12). Recently, Bates and colleagues (13) showed that lung function is relatively insensitive to the amount of tissue loss in the beginning of the destruction process. They demonstrated that lung compliance could stay relatively normal during the early phase of the disease until microscopic alterations reach a critical level, beyond which a rapid decline in function occurs. If lung function is decoupled from the amount of tissue loss, the question arises whether it is the ECM composition, ECM organization within the alveolar wall, or some feature of the alveolar wall network that determines lung function decline. Furthermore, it is equally MK-0679 (Verlukast) unclear whether there is a specific mechanism that drives changes in structure that also influences function. Suki and colleagues (14) proposed that mechanical causes in the emphysematous lung contribute to the progressive nature of the disease by rupturing the remodeled alveolar walls, thus reducing tissue stiffness. They also suggested that for this mechanism to work, the weakening of collagen, a key load-bearing ECM molecule, is necessary. In this study, we hypothesized that practical changes in emphysema are related to both the degree of collagen redesigning and specific localized alterations in alveolar airspace structure. To test this hypothesis, we tracked the redesigning of collagen and elastin, the detailed alveolar structure, and lung function in mice during 3 weeks after elastolytic injury. The results were interpreted using a network model of the parenchyma. == Materials and Methods == == Animal Preparation == Six groups of C57BL/6 mice were used. Procedures were approved by the Animal MK-0679 (Verlukast) Care and Use Committee of Boston University or college (Boston, MA). Mice were treated with oropharyngeal instillation of either 0.25 IU of porcine pancreatic elastase (PPE) (n= 18) or phosphate-buffered saline (saline control) (n= 18). Animals were killed at 2, 7, and 21 days after treatment. == Respiratory Mechanics == Mice were anesthetized, tracheostomized, and ventilated. Respiratory impedance was measured at five positive end-expiratory pressure (PEEP) levels using pressured oscillations (15). A model including a heterogeneous distribution of MK-0679 (Verlukast) cells elastance (16) was match to the data, providing estimations of airway resistance (Uncooked), hysteresivity, a imply tissue compliance (Cmean), and a minimum (Cmin) and a maximum compliance (Cmax)..