The Endothelin A Receptor Mediates Fibrocyte Differentiation in Chronic Obstructive Asthma. The Involvement of Connective Tissue Growth Factor

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Abstract

Rationale:

Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)+ 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 α-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. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared 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 α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-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.

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