Abstract
The purpose of this study was to determine how the initial distribution of elastase in mouse lungs determines the time course of tissue destruction and how structural heterogeneity at different spatial scales influences lung function. We evaluated lung function and alveolar structure in normal and emphysematous C57BL/6 mice at 2 and 21 days following orotracheal treatment with porcine pancreatic elastase (PPE). Initial distribution of elastase 1 h after treatment was assessed using red fluorescently labeled PPE (f-PPE) by laser scanning confocal microscopy. From measured input impedance of the respiratory system, the global lung compliance, and the variability of regional compliance were obtained. Lungs were fixed and equivalent airspace diameters were measured in four lobes of the right lung and three regions of the left lung. At day 2 and day 21, the mean airspace diameter of each region was significantly enlarged which was accompanied by an increased inter-regional heterogeneity. The deposition of f-PPE on day 0 was much more heterogeneous than the inter-regional diameters at both day 2 and day 21 and, at day 21, this reached statistical significance (p < 0.05). Microscale heterogeneity characterized by the overall variability of airspace diameters correlated significantly better with compliance than macroscale or inter-regional heterogeneity. Furthermore, while the spatial distribution of the inflammatory response does not seem to follow that of the elastase deposition, it correlates with the strongest regional determinant of lung function. These results may help interpret lung function decline in terms of structural deterioration in human patients with emphysema.
Highlights
Mouse models are useful for investigating the mechanisms of disease pathogenesis or progression
Upper lung predominant emphysema is quite common in cigarette smoke induced emphysema (Mohamed Hoesein et al, 2012), whereas lower predominance is more common in alpha1 antitrypsin deficiency patients (Bakker et al, 2008)
A recent study showed that there are some patients with a homogeneous pattern of distribution of emphysema and these patients appear to have a rapid decline in lung function (Tanabe et al, 2012)
Summary
Mouse models are useful for investigating the mechanisms of disease pathogenesis or progression. The cigarette smoke-induced effects of enzymes in the lung are often mimicked by treating mice with elastase (Lucattelli et al, 2003; Ito et al, 2005; Hantos et al, 2008; Yao et al, 2010; Hamakawa et al, 2011) While this model has obvious limitations, it is useful to investigate the time course of structural changes in the lung tissue due to the fast progression of emphysema. It is possible that mechanical failure causes small scale heterogeneity at the level of tens of alveoli whereas the initial distribution of elastase contributes to large scale heterogeneity such as inter-lobar variations in structure It is not known which of these processes dominate the time course of the overall structural deterioration of the lung
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