Increased endothelin-1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats

Endothelin-1 (Et-1) has been implicated in the pathogenesis of pulmonary fibrosis with increased levels in the lung tissue of patients with pulmonary fibrosis and profibrotic effects in vitro. In this study we have investigated the temporal changes in lung Et-1 levels and immunohistochemical localization in relation to collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung Et-1 content doubled by 3 d following the intratracheal instillation of bleomycin, and continued to increase up to 7 d when values were about threefold greater than controls. Thereafter, the values for bleomycin-treated animals remained constant up to 21 d. There was no change in collagen content at 3 d but after 7 d there was a 25% increase and by 21 d levels were almost double those of the controls. In normal lung, Et-1 was predominantly associated with epithelial cells of conducting and nonconducting airways. Following bleomycin administration, intense staining of macrophages and conducting airway and alveolar epithelial cells was observed with marked staining of perivascular, peribronchiolar, and alveolar septal connective tissue, as well as the venular and arterial intima and media. These results demonstrate elevation of Et-1 levels prior to an increase in collagen content which, along with its localization within developing fibrotic lesions, provides further evidence of a profibrotic role for Et-1 in the pathogenesis of pulmonary fibrosis.