INCREASED ENDOTHELIN-1 IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS AND THE EFFECT OF AN ENDOTHELIN RECEPTOR ANTAGONIST

Idiopathic pulmonary fibrosis (IPF) is characterized by an alveolitis with epithelial and endothelial damage progressing to fibrosis. Numero us mediators have been implicated in this complex process. Studies in humans have shown that endothelin-l (ET-1), a vasoconstrictor and mito genic peptide, is a mediator in IPF. To determine the role of ET-1 and endothelin-converting enzyme (ECE)-1 and the effect of bosentan, an E T receptor antagonist, in an animal model of IPF, we studied three gro ups of rats (n = 6 each): Group 1, control, received saline; Group 2, fibrosis, received 1.5 U bleomycin intratracheally; Group 3, fibrosis- bosentan treated, received bleomycin and bosentan daily by gavage. Aft er 28 d, right upper lobes were fixed for immunohistochemistry (IHC) a nd sections were stained with antisera to ET-1 and ECE-1 and graded se miquantitatively. Sections from left lungs were embedded in paraffin a nd stained for light microscopic morphometry to quantitate the fibrosi s. By IHC, we found increased ET-1 immunoreactivity (ir) in airway epi thelium and inflammatory cells, and ECE-l-ir in airway epithelium, typ e II pneumocytes and endothelial cells (p < 0.05). By morphometry, the volume fraction (Vv) of connective tissue (CT) increased and the Vv o f air decreased in the fibrosis group compared with that in the contro l group. Bosentan reduced the Vv of CT and increased the Vv of air com pared with that in the fibrosis group (p < 0.05). These results indica te that ET-1 is involved in the pathogenesis of pulmonary fibrosis in the rodent model and that blockage of its receptors reduces the fibros is.