title: Is neutrophil elastase the missing link between emphysema and fibrosis? Evidence from two mouse models.
abstract: BACKGROUND
  The separation of emphysema from fibrosis is not as clear-cut as it was thought in early studies. These two pathologies may be present at the same time in human lungs and in mice either instilled with elastolytic enzymes or bleomycin or exposed to cigarette-smoke. According to a current view, emphysema originates from a protease/antiprotease imbalance, and a role for antiproteases has also been suggested in the modulation of the fibrotic process. In this study we investigate in experimental animal models of emphysema and fibrosis whether neutrophil elastase may constitute a pathogenic link between these two pathologies.
  
  
  METHODS
  This study was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (BLM) or by chronic exposure to cigarette-smoke. In order to assess the protease-dependence of the BLM-induced lesion, a group mice was treated with 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine proteinase inhibitor active toward neutrophil elastase. Lungs from each experimental group were used for the immunohistochemical assessment of transforming growth factor-beta (TGF-beta) and transforming growth factor-alpha (TGF-alpha) and for determination of the mean linear intercept as well as the percent volume densities of fibrosis and of emphysematous changes. Additionally, the lungs were also assessed for desmosine content and for the determination of elastase levels in the pulmonary interstitium by means of immunoelectron microscopy.
  
  
  RESULTS
  We demonstrate that in BLM-treated mice (i) the development of elastolytic emphysema precedes that of fibrosis; (ii) significant amount of elastase in alveolar interstitium is associated with an increased expression of TGF-beta and TGF-alpha; and finally, (iii) emphysematous and fibrotic lesions can be significantly attenuated by using a protease inhibitor active against neutrophil elastase. Also, in a strain of mice that develop both emphysema and fibrosis after chronic cigarette-smoke exposure, the presence of elastase in alveolar structures is associated with a positive immunohistochemical reaction for reaction for both TGF-beta and TGF-alpha.
  
  
  CONCLUSIONS
  The results of the present study strongly suggest that neutrophil elastase may represent a common pathogenic link between emphysema and fibrosis. Proteases and in particular neutrophil elastase could act as regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells resulting either in emphysema or in fibrosis or both.
authors.affiliation: Department of Physiopathology and Experimental Medicine, University of Siena, 53100 Siena, Italy. lucattelli@unisi.it
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Bartalesi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cavarra
authors.forename: Silvia
authors.initials: S
authors.lastname: Fineschi
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lunghi
authors.forename: Piero A
authors.initials: PA
authors.lastname: Martorana
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
mesh_terms: D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D004646:Emphysema / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D019317:Evidence-Based Medicine / Q000379:methods; D019272:Leukocyte Elastase / Q000097:blood*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D012906:Smoke; D014026:Nicotiana
chemical_list: D012906:Smoke; D001761:Bleomycin; D019272:Leukocyte Elastase