title: Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kambas
authors.forename: Akrivi
authors.initials: A
authors.lastname: Chrysanthopoulou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kourtzelis
authors.forename: Marianna
authors.initials: M
authors.lastname: Skordala
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mitroulis
authors.forename: Stavros
authors.initials: S
authors.lastname: Rafail
authors.forename: Stergios
authors.initials: S
authors.lastname: Vradelis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Sigalas
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Wu
authors.forename: Matthaios
authors.initials: M
authors.lastname: Speletas
authors.forename: George
authors.initials: G
authors.lastname: Kolios
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ritis
mesh_terms: D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013917:Thrombin / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
chemical_list: C488033:C5AR1 protein, human; C526317:CCN2 protein, human; D019332:Endothelin-1; D044087:Receptor, Anaphylatoxin C5a; D044463:Receptor, PAR-1; D011951:Receptors, Complement; D055513:Connective Tissue Growth Factor; D049452:Green Fluorescent Proteins; D015936:Complement C5a; D013925:Thromboplastin; D013917:Thrombin