Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist

Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):600-8. doi: 10.1164/ajrccm.156.2.9607123.


Idiopathic pulmonary fibrosis (IPF) is characterized by an alveolitis with epithelial and endothelial damage progressing to fibrosis. Numerous mediators have been implicated in this complex process. Studies in humans have shown that endothelin-1 (ET-1), a vasoconstrictor and mitogenic 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 ET receptor antagonist, in an animal model of IPF, we studied three groups 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. After 28 d, right upper lobes were fixed for immunohistochemistry (IHC) and sections were stained with antisera to ET-1 and ECE-1 and graded semiquantitatively. Sections from left lungs were embedded in paraffin and stained for light microscopic morphometry to quantitate the fibrosis. By IHC, we found increased ET-1 immunoreactivity (ir) in airway epithelium and inflammatory cells, and ECE-1-ir in airway epithelium, type II pneumocytes and endothelial cells (p < 0.05). By morphometry, the volume fraction (Vv) of connective tissue (CT) increased and the Vv of air decreased in the fibrosis group compared with that in the control group. Bosentan reduced the Vv of CT and increased the Vv of air compared with that in the fibrosis group (p < 0.05). These results indicate that ET-1 is involved in the pathogenesis of pulmonary fibrosis in the rodent model and that blockage of its receptors reduces the fibrosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents
  • Aspartic Acid Endopeptidases / metabolism
  • Bleomycin
  • Bosentan
  • Drug Evaluation, Preclinical
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / metabolism*
  • Endothelin-Converting Enzymes
  • Immunohistochemistry
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Metalloendopeptidases / metabolism
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Rats
  • Rats, Inbred F344
  • Sulfonamides / therapeutic use*


  • Anti-Bacterial Agents
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Sulfonamides
  • Bleomycin
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Endothelin-Converting Enzymes
  • Bosentan