Structure–Function Relations in an Elastase-Induced Mouse Model of Emphysema

Abstract

Emphysema is a progressive disease characterized by the destruction of peripheral airspaces and subsequent decline in lung function. However, the relation between structure and function during disease progression is not well understood. The objective of this study was to assess the time course of the structural, mechanical, and remodeling properties of the lung in mice after elastolytic injury. At 2, 7, and 21 days after treatment with porcine pancreatic elastase, respiratory impedance, the constituents of lung extracellular matrix, and histological sections of the lung were evaluated. In the control group, no changes were observed in the structural or functional properties, whereas, in the treatment group, the respiratory compliance and its variability significantly increased by Day 21 (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. Structure-function relations manifested themselves in strong correlations between compliance parameters and both mean size and heterogeneity of airspace structure (r 2 . 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, forceinduced failure of remodeled collagen.

Proteoglycans Maintain Lung Stability in an Elastase-Treated Mouse Model of Emphysema

“…The organ level functional changes in R and C due to PPE treatment were similar to those in tight-skin (24), SP-D-deficient (25), TNF-a-overexpressing (26), and elastase-treated (21,23) mice. These functional changes have structural origins (21,23,27,28).…”

“…These functional changes have structural origins (21,23,27,28). Tissue destruction in emphysema leads to a spatially heterogeneous structure (29) with variability in airspace sizes (20,21,30,31).…”

“…Animal models also suggest that surface tension is perhaps not very important in emphysema (23,34). Indeed, PPE-induced changes in the pressure-volume curve are similar to the change in the stress-strain curve in emphysema (14).…”

“…Although computer models have been used to study structure-function relations in emphysema (23,46), the role of PGs has not been evaluated. Our network simulations ( Figure 7) aimed to clarify how alterations in PGs affect structure and function characterized by D 2 and C, respectively, under mechanical force-based destruction.…”

Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice

“…We previously reported that inhaled PC-SOD could suppress PPE-induced pulmonary emphysema even when the treatment protocol was started 3 days after the administration of PPE (39). However, because PPE-induced pulmonary dysfunction becomes clear 7-21 days after the PPE treatment (14), the therapeutic effect of the drug should be examined at stage later than day 3. Therefore, in the present study, PC-SOD treatment was commenced 14 days after the administration of PPE, and pulmonary emphysema and lung mechanics were assessed on day 21.…”