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

doi:10.4049/jimmunol.1003756

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

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	6568-75
Number of pages	8
Journal	Journal of Immunology
Volume	186
Issue number	11
DOIs	https://doi.org/10.4049/jimmunol.1003756
Publication status	Published - 1 Jun 2011

Keywords

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

Access to Document

10.4049/jimmunol.1003756

Cite this

Kambas, K., Chrysanthopoulou, A., Kourtzelis, I., Skordala, M., Mitroulis, I., Rafail, S., Vradelis, S., Sigalas, I., Wu, Y.-Q., Speletas, M., Kolios, G., & Ritis, K. (2011). Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade. Journal of Immunology, 186(11), 6568-75. https://doi.org/10.4049/jimmunol.1003756

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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.",

keywords = "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",

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

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doi = "10.4049/jimmunol.1003756",

language = "English",

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Kambas, K, Chrysanthopoulou, A, Kourtzelis, I, Skordala, M, Mitroulis, I, Rafail, S, Vradelis, S, Sigalas, I, Wu, Y-Q, Speletas, M, Kolios, G & Ritis, K 2011, 'Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade', Journal of Immunology, vol. 186, no. 11, pp. 6568-75. https://doi.org/10.4049/jimmunol.1003756

TY - JOUR

T1 - Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade

AU - Kambas, Konstantinos

AU - Chrysanthopoulou, Akrivi

AU - Kourtzelis, Ioannis

AU - Skordala, Marianna

AU - Mitroulis, Ioannis

AU - Rafail, Stavros

AU - Vradelis, Stergios

AU - Sigalas, Ioannis

AU - Wu, You-Qiang

AU - Speletas, Matthaios

AU - Kolios, George

AU - Ritis, Konstantinos

PY - 2011/6/1

Y1 - 2011/6/1

N2 - 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.

AB - 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.

KW - Blotting, Western

KW - Bronchoalveolar Lavage Fluid/chemistry

KW - Bronchopulmonary Dysplasia/genetics

KW - Cells, Cultured

KW - Colon/metabolism

KW - Complement C5a/genetics

KW - Connective Tissue Growth Factor/genetics

KW - Endothelin-1/genetics

KW - Female

KW - Fibrosis

KW - Green Fluorescent Proteins/genetics

KW - Humans

KW - Immunohistochemistry

KW - Infant, Newborn

KW - Lung/metabolism

KW - Male

KW - Microscopy, Fluorescence

KW - Myofibroblasts/metabolism

KW - Receptor, Anaphylatoxin C5a

KW - Receptor, PAR-1/genetics

KW - Receptors, Complement/genetics

KW - Respiratory Distress Syndrome, Newborn/genetics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Signal Transduction

KW - Thrombin/genetics

KW - Thromboplastin/genetics

U2 - 10.4049/jimmunol.1003756

DO - 10.4049/jimmunol.1003756

M3 - Article

C2 - 21531894

SN - 0022-1767

VL - 186

SP - 6568

EP - 6575

JO - Journal of Immunology

JF - Journal of Immunology

IS - 11

ER -