Pneumologie 2011; 65 - A8
DOI: 10.1055/s-0031-1296099

Prolonged Development of Elastase-Induced Emphysema is Supported by Increased Apoptosis

A Bohla 1, K Kohse 1, O Eickelberg 1, 2, AÖ Yildirim 1
  • 1Comprehensive Pneumology Center, Institute of Lung Biology and Disease
  • 2Institute of Experimental Pneumology, Klinikum der Universität München, Helmholtz Zentrum München

Introduction: Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is characterized amongst others by development of emphysema, which is known to occur as a result of imbalance of proteases and antiproteases. There are a variety of enzymes like neutrophil elastase (NE) and matrix metalloprotease 12 (MMP-12), which are capable of destroying parenchymal tissue, causing loss of alveolae and airway enlargement in the lung. We showed that a single application of porcine pancreatic elastase (PPE) causes a severe emphysema-like phenotype in C57BL/6 mice (Yildirim et al. 2010, AJRCCM). Since the development of emphysema is apparently not completed after elastase application, we aimed to identify possible key mechanisms that drive this process even at late time points.

Methods: Female C57BL/6N mice received a single oropharyngeal application of PPE. Animals in control groups were given a comparable volume of PBS. Development of emphysema was assessed by lung function measurements using Buxco and FlexiVent systems, and stereological analysis of lung tissue on several time points until 23 weeks after application. Molecular markers for proliferation, apoptosis and extracellular matrix were measured by quantitative real time PCR.

Results: PPE-treated mice showed a continuous decline in pulmonary function parameters like compliance. Airway enlargement was reflected in increase of total lung capacity (TLC) or functional residual capacity (FRC). Stereological analysis of lung tissue of mice presenting progressing loss of alveolar septae and the resulting airway enlargement until 23 weeks after application of PPE supported these findings. QRT-PCR revealed elevated expression of apoptosis markers and MMP-12, reduced proliferation and increased expression of matrix components.

Conclusion: Mice treated with a single application of porcine pancreatic elastase developed pulmonary emphysema, characterized by continuous loss of alveolar septae and according impairment of lung function parameters. The progression of emphysema at later time points was presumably driven by elevated MMP-12 expression levels, reduced cell proliferation and increased apoptosis.