Induction of emphysema in hamsters by intratracheal instillation of cathepsin B

Current theories of pathogenesis suggest that pulmonary emphysema develops in humans because of progressive loss or derangement of lung elastin through a process mediated by elastolytic enzymes released by inflammatory cells. Neutrophils are considered primary etiologic factors because these cells produce and release two potent serine proteinases that cause emphysema when instilled into the lungs of animals. It has been suggested that alveolar macrophages also contribute to the development of emphysema through production of several enzymes with elastolytic activity, including the lysosomal cysteine proteinases cathepsin B and cathepsin L, but this has not been verified experimentally. In the current study, we instilled 115 μg of active cathepsin B into the lungs of hamsters three times at 48-h intervals. After 6 wk microscopic evaluation revealed that lung sections of five of seven animals given cathepsin B contained focal areas of enlarged and distorted alveoli, in the absence of fibrosis, which were similar to changes seen in the lungs of animals given papain intratracheally. Morphometrically, mean linear intercept (μm) values were significantly higher (p < 0.025) in animals given cathepsin B (204.4 ± 20.8) as compared with control animals (173.2 ± 7.8), and internal surface area (sqcm) values were significantly lower (935 ± 120 versus 1,083 ± 56 in control animals), thereby confirming that airspace enlargement had developed after instillation of the enzyme. Lung volumes (ml) and compliance (ml/cm H₂O) were not significantly higher in animals given cathepsin B. The current findings, along with additional observations that the number of alveolar macrophages are increased in the lungs of cigarette smokers and that the cells contain higher levels of cathepsin B, suggest that alveolar macrophages may participate in the development of emphysema and that cysteine proteinases contained within these cells could exert elastolytic activity, thereby contributing to the process.