Estimating structural alterations in animal models of lung emphysema. Is there a gold standard?

Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases. The major component of COPD, which affects the gas-exchanging parenchyma of the lung, emphysema, is characterized by destruction of alveolar septae leading to loss of functional surface, loss of alveoli and enlargement of remaining distal airspaces. These microstructural alterations can be modeled in animals and can be measured using stereological methods applied to imaging datasets. Many animal models of emphysema exist, but most of them are insufficiently characterized with respect to the underlying nature (e.g. destructive or developmental) and the degree of the structural alterations. The most popular parameter for assessment of emphysematous alterations, mean linear intercept length, has severe limitations. It can, therefore, not be recommended. Better design-based stereological alternatives exist but are less often applied, such as total volumes of parenchymal compartments (alveolar airspace, alveolar duct airspace, alveolar septum), total alveolar surface area, total alveolar number and mean alveolar size and its size variation. A prerequisite is the use of appropriate fixation, sampling, and specimen processing protocols. This article reviews the challenges of stereologic assessment of emphysematous alterations in the lung and illustrates possible strategies.