DOES NEUTROPHIL ELASTASE CONSTITUTE A PATHOGENIC LINK BETWEEN EMPHYSEMA AND FIBROSIS? EVIDENCE FROM ANIMAL MODELS

ecent data suggest that the separation of emphysema from fibrosis is not as it was thought in early studies. These two pathologies may be present at the same time in human lungs, in lungs of mice after cigarette-smoke or bleomycin (BLM) 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 changes. In this study we investigate whether neutrophil elastase may constitute a pathogenic link between these two pathologies. This was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (Cavarra et al. ERJ , 2001) or cigarette-smoke (Bartalesi et al. ERJ, 2005). In particular, we demonstrate that in bleomycin-treated mice (i) the development of elastolytic emphysema precedes that of fibrosis; (ii) alveolar elastase burden is associated with an increased expression of transforming growth factor-β (TGF-β) and transforming growth factor-α (TGF-α); and finally, (iii) emphysematous and fibrotic lesions can be significantly attenuated by using an elastase inhibitor. Similarly, in mice that develop both emphysema and fibrosis after cigarette-smoke exposure an immunohistochemical reaction for elastase is associated with a positive reaction for TGF-β and TGF-α. These data indicate that neutrophil elastase represents a common pathogenic link between emphysema and fibrosis. In conclusion, proteases and in particular elastase may constitute important regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells.