Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade

Konstantinos Kambas, Akrivi Chrysanthopoulou, Ioannis Kourtzelis, Marianna Skordala, Ioannis Mitroulis, Stavros Rafail, Stergios Vradelis, Ioannis Sigalas, You-Qiang Wu, Matthaios Speletas, George Kolios, Konstantinos Ritis

Research output: Contribution to journalArticlepeer-review


Neonatal respiratory distress syndrome can progress to bronchopulmonary dysplasia (BPD), a serious pulmonary fibrotic disorder. Given the involvement of the extrinsic coagulation cascade in animal models of lung fibrosis, we examined its role in BPD. We observed a higher number of neutrophils expressing tissue factor (TF) in bronchoalveolar lavage fluid (BALF) from infants with BPD than from those with uncomplicated respiratory distress syndrome together with a parallel decrease in TF and connective tissue growth factor (CTGF) in BALF supernatants during the disease course. The involvement of coagulation in the fibrotic process associated with BPD was further evaluated by treating primary human colonic myofibroblasts with BALF supernatants from infants with BPD. These human colonic myofibroblasts demonstrated an enhanced C5a- and thrombin-dependent migration. Moreover, they expressed TF in an endothelin-1-dependent manner, with subsequent activation of the extrinsic coagulation cascade and CTGF production mediated by protease-activator receptor-1 signaling. These data provide a novel mechanism for the development of BPD and indicate that endothelin-1 signaling contributes to fibrosis by upregulating a TF/thrombin amplification loop responsible for CTGF production, and offer novel and specific therapeutic targets for pulmonary fibrotic disease.

Original languageEnglish
Pages (from-to)6568-75
Number of pages8
JournalJournal of Immunology
Issue number11
Publication statusPublished - 1 Jun 2011


  • Blotting, Western
  • Bronchoalveolar Lavage Fluid/chemistry
  • Bronchopulmonary Dysplasia/genetics
  • Cells, Cultured
  • Colon/metabolism
  • Complement C5a/genetics
  • Connective Tissue Growth Factor/genetics
  • Endothelin-1/genetics
  • Female
  • Fibrosis
  • Green Fluorescent Proteins/genetics
  • Humans
  • Immunohistochemistry
  • Infant, Newborn
  • Lung/metabolism
  • Male
  • Microscopy, Fluorescence
  • Myofibroblasts/metabolism
  • Receptor, Anaphylatoxin C5a
  • Receptor, PAR-1/genetics
  • Receptors, Complement/genetics
  • Respiratory Distress Syndrome, Newborn/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thrombin/genetics
  • Thromboplastin/genetics

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