Abstract

Rationale: Fibrocytes possess increased differentiability into a-smooth muscle actin (a-SMA)1 myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin- 1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. Objectives: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. Methods: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or a-SMA were identified by flow cytometry. Measurements and Main Results: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serumlevels of ET-1andthe expression of the ETARinfibrocyteswere significantly higher in patients withCOAcompared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and a-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated a-SMA expression induced by ET-1 in fibrocytes from normal participants. Conclusions: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

Original languageEnglish
Pages (from-to)298-308
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume188
Issue number3
DOIs
Publication statusPublished - Aug 1 2013

Fingerprint

Connective Tissue Growth Factor
Endothelin Receptors
Asthma
Smooth Muscle
Actins
Endothelin-1
Fibrosis
Myofibroblasts
Growth Factor Receptors
Pulmonary Fibrosis
Flow Cytometry
Collagen
Fibroblasts
Gene Expression

Keywords

  • A-smooth muscle actin
  • Chronic obstructive asthma
  • Connective tissue growth factor
  • Endothelin A receptor
  • Fibrocyte

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{2ec2b0ed991a404799fbce4d76097a80,
title = "The endothelin a receptor mediates fibrocyte differentiation in chronic obstructive asthma the involvement of connective tissue growth factor",
abstract = "Rationale: Fibrocytes possess increased differentiability into a-smooth muscle actin (a-SMA)1 myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin- 1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. Objectives: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. Methods: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or a-SMA were identified by flow cytometry. Measurements and Main Results: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serumlevels of ET-1andthe expression of the ETARinfibrocyteswere significantly higher in patients withCOAcompared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and a-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated a-SMA expression induced by ET-1 in fibrocytes from normal participants. Conclusions: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.",
keywords = "A-smooth muscle actin, Chronic obstructive asthma, Connective tissue growth factor, Endothelin A receptor, Fibrocyte",
author = "Weng, {Chih Ming} and Chen, {Bing Chang} and Wang, {Chun Hua} and Feng, {Po Hao} and Lee, {Meng Jung} and Huang, {Chien Da} and Kuo, {Han Pin} and Lin, {Chien Huang}",
year = "2013",
month = "8",
day = "1",
doi = "10.1164/rccm.201301-0132OC",
language = "English",
volume = "188",
pages = "298--308",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "3",

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TY - JOUR

T1 - The endothelin a receptor mediates fibrocyte differentiation in chronic obstructive asthma the involvement of connective tissue growth factor

AU - Weng, Chih Ming

AU - Chen, Bing Chang

AU - Wang, Chun Hua

AU - Feng, Po Hao

AU - Lee, Meng Jung

AU - Huang, Chien Da

AU - Kuo, Han Pin

AU - Lin, Chien Huang

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Rationale: Fibrocytes possess increased differentiability into a-smooth muscle actin (a-SMA)1 myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin- 1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. Objectives: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. Methods: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or a-SMA were identified by flow cytometry. Measurements and Main Results: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serumlevels of ET-1andthe expression of the ETARinfibrocyteswere significantly higher in patients withCOAcompared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and a-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated a-SMA expression induced by ET-1 in fibrocytes from normal participants. Conclusions: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

AB - Rationale: Fibrocytes possess increased differentiability into a-smooth muscle actin (a-SMA)1 myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin- 1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. Objectives: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. Methods: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or a-SMA were identified by flow cytometry. Measurements and Main Results: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serumlevels of ET-1andthe expression of the ETARinfibrocyteswere significantly higher in patients withCOAcompared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and a-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated a-SMA expression induced by ET-1 in fibrocytes from normal participants. Conclusions: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

KW - A-smooth muscle actin

KW - Chronic obstructive asthma

KW - Connective tissue growth factor

KW - Endothelin A receptor

KW - Fibrocyte

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