β2-肾上腺素能受体激动剂对重度哮喘患者纤维细胞功能的抑制作用降低
2018/01/08
摘要
背景：尽管接受高剂量皮质类固醇激素和长效β2-肾上腺素受体（AR）激动剂（LABAs）治疗，重症哮喘患者气道重塑增加，循环纤维细胞数量增加，肌纤维母细胞分化能力增强。本王呢旨在确定β2-AR激动剂单用或与皮质类固醇联用对纤维细胞功能的作用。
方法：在健康受试者和非重症或重症哮喘患者中分离的外周血单核细胞的非粘附性非T细胞用β2-AR激动剂沙美特罗单用或联用皮质类固醇地塞米松治疗。使用流式细胞术测定纤维细胞（胶原I + / CD45 +细胞）和分化的纤维细胞（α-平滑肌肌动蛋白+细胞）的数目以及CC趋化因子受体7和β2-AR的表达。使用cAMP类似物8-溴腺苷3'，5'-环一磷酸（8-Br-cAMP）和IV型磷酸二酯酶（PDE4）抑制剂咯利普兰来阐明环腺苷酸（cAMP）的作用。
结果:沙美特罗减少健康受试者和非重症哮喘患者的增殖，肌成纤维细胞分化和纤维细胞的CCR7表达。重症哮喘患者的纤维细胞具有较低的基线表面β2-AR表达，并且对沙美特罗相对不敏感，但对8-Br-cAMP或咯利普兰敏感。地塞米松增加β2-AR的表达，增强沙美特罗对重症哮喘患者纤维细胞分化的抑制作用。
结论：重症哮喘患者的纤维细胞对沙美特罗的抑制作用相对不敏感，通过与皮质类固醇联合可逆转这种作用。
Reduced suppressive effect of β2-adrenoceptor agonist on fibrocyte function in severe asthma.
Lo CY1,2, Michaeloudes C1, Bhavsar PK3,4, Huang CD2, Chang PJ1,2, Wang CH2, Kuo HP2, Chung KF1.
Abstract
BACKGROUND:Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.
METHODS:Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.
RESULTS:Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.
CONCLUSIONS:Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
背景：尽管接受高剂量皮质类固醇激素和长效β2-肾上腺素受体（AR）激动剂（LABAs）治疗，重症哮喘患者气道重塑增加，循环纤维细胞数量增加，肌纤维母细胞分化能力增强。本王呢旨在确定β2-AR激动剂单用或与皮质类固醇联用对纤维细胞功能的作用。
方法：在健康受试者和非重症或重症哮喘患者中分离的外周血单核细胞的非粘附性非T细胞用β2-AR激动剂沙美特罗单用或联用皮质类固醇地塞米松治疗。使用流式细胞术测定纤维细胞（胶原I + / CD45 +细胞）和分化的纤维细胞（α-平滑肌肌动蛋白+细胞）的数目以及CC趋化因子受体7和β2-AR的表达。使用cAMP类似物8-溴腺苷3'，5'-环一磷酸（8-Br-cAMP）和IV型磷酸二酯酶（PDE4）抑制剂咯利普兰来阐明环腺苷酸（cAMP）的作用。
结果:沙美特罗减少健康受试者和非重症哮喘患者的增殖，肌成纤维细胞分化和纤维细胞的CCR7表达。重症哮喘患者的纤维细胞具有较低的基线表面β2-AR表达，并且对沙美特罗相对不敏感，但对8-Br-cAMP或咯利普兰敏感。地塞米松增加β2-AR的表达，增强沙美特罗对重症哮喘患者纤维细胞分化的抑制作用。
结论：重症哮喘患者的纤维细胞对沙美特罗的抑制作用相对不敏感，通过与皮质类固醇联合可逆转这种作用。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(Respir Res. 2017 Nov 21;18(1):194. doi: 10.1186/s12931-017-0678-7. [Epub ahead of print])
(Respir Res. 2017 Nov 21;18(1):194. doi: 10.1186/s12931-017-0678-7. [Epub ahead of print])
Reduced suppressive effect of β2-adrenoceptor agonist on fibrocyte function in severe asthma.
Lo CY1,2, Michaeloudes C1, Bhavsar PK3,4, Huang CD2, Chang PJ1,2, Wang CH2, Kuo HP2, Chung KF1.
Abstract
BACKGROUND:Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.
METHODS:Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.
RESULTS:Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.
CONCLUSIONS:Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
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