Is there a pathogenic link between emphysema and fibrosis? Evidence from animal models.

Recent data suggest that the separation of emphysema from fibrosis is not as clear-cut as it has appeared to be in early studies. In fact, both these pathologies may be present at the same time in human lungs, in lungs of mice after cigarette-smoke or bleomycin exposure, or in mouse lungs instilled with elastolytic enzymes. According to the current view, pulmonary emphysema originates from an imbalance between elastinolytic proteases and their inhibitors. Recently. a significant role for the antiproteases was also suggested in the modulation of fibrotic lesions. We previously reported that BLM administration induced in α1-PI deficient mice alveolitis and fibrosis. It also resulted in enlargement of air spaces that may be due to loss of alveolar septa and/or retraction forces generated by the fibrotic process. We recently demonstrated that the development of “true” elastolytic emphysema precedes that of fibrosis in α1-PI deficient mice. The further deterioration of these changes can be ascribed to the retraction forces of the fibrotic process. After BLM administration, we observed a significant change of a number of cytokines and cytokine receptors related to the neutrophil elastase activity. These cytokines were detected in foci of cellular proliferation and in areas of subpleural fibrosis when an increase of the elastase burden could be demonstrated. A similar cytokine profile has been detected in mice that develop foci of subpleural fibrosis after cigarette-smoke. In conclusion, proteases and in particular elastase may constitute important regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells.