Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Am J Respir Crit Care Med. 2013 Aug 1;188(3):298-308. doi: 10.1164/rccm.201301-0132OC.
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.
To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA.
Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry.
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.
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.
成纤维细胞在慢性阻塞性哮喘（COA）中具有向α-平滑肌肌动蛋白（α-SMA）（+）肌成纤维细胞分化的能力增加，并有助于肺纤维化。内皮素-1（ET-1）通过 ETA 受体（ETAR）诱导基质相关基因表达，并促进成纤维细胞分化。然而，成纤维细胞分化的机制尚不清楚。
定义 ETAR 和结缔组织生长因子（CTGF）在 COA 纤维化发展中成纤维细胞中的作用。
分离血液非黏附非-T（NANT）细胞，并通过流式细胞术鉴定表达 CD45、胶原 I、CTGF、ETAR 或 α-SMA 的成纤维细胞。
我们显示了支气管壁中成纤维细胞的积累和 COA 患者成纤维细胞中 CTGF 的过度表达。培养后，COA 患者的成纤维细胞中 CTGF 增加，但正常参与者或无阻塞性哮喘患者的成纤维细胞中则没有增加。COA 患者的 ET-1 血清水平和 ETAR 在成纤维细胞中的表达明显高于正常参与者和无阻塞性哮喘患者。用 ETAR 拮抗剂（BQ123）治疗，而不是 ETBR 拮抗剂（BQ788），可降低 COA 患者成纤维细胞中 CTGF 和 α-SMA 的表达以及成纤维细胞分化。此外，BQ123 或抗 CTGF 抗体治疗可减弱 ET-1 诱导的正常参与者成纤维细胞中 α-SMA 的表达。
我们的研究结果首次表明，ETAR 途径对于 CTGF 表达至关重要，这导致了 COA 中成纤维细胞的分化，并表明 ETAR 拮抗剂可能是预防 COA 患者纤维化发展的潜在抗纤维化药物。
