Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.
Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.
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DOI：
10.1016/j.jaci.2009.06.022
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Robinson DS
中科院分区：
文献类型：
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作者：
Kariyawasam HH;Pegorier S;Barkans J;Xanthou G;Aizen M;Ying S;Kay AB;Lloyd CM;Robinson DS
转化生长因子（TGF）-β 1和激活素A均与哮喘的气道重塑有关，但疾病激活后其特异性信号通路的调节仍不明确。确定过敏原激发后哮喘气道中TGF-β 1、激活素A配体和卵泡抑素（天然激活素抑制剂）及其I型和II型受体（ALK-1、ALK-5和ALK-4以及T β RII和ActRIIA/RIIB）的表达动力学以及信号传导激活（通过pSmad 2）。对15例轻度特应性哮喘患者（中位年龄25岁，中位FEV1%预测值97%）的支气管活检标本进行免疫组化检测。使用培养的正常人支气管上皮（NHBE）细胞评价激活素A的功能作用。pSmad2+上皮细胞在24小时增加（p = 0.03），并且在粘膜下细胞中检测到pSmad2。未证实激活素A、卵泡抑素或TGF-β 1表达的调节。过敏原激发后激活素受体+细胞增加。上皮（p = 0.04）和粘膜下层（p = 0.04）中的ALK-4和上皮（p = 0.01）中的ActRIIA。在基线和激发后，粘膜下层中的TGF-β受体ALK-5表达极轻微，激发后在上皮中下调（p = 0.02），而在变应原激发后，粘膜下层中的ALK-1和T β RII表达增加（分别为p = 0.03和p = 0.004）。过敏原激发后，T细胞的ALK-1和ALK-4表达增加。激活素A诱导NHBE细胞增殖，由NHBE细胞响应TNF-α产生，并下调TNF-α和IL-13诱导的NHBE细胞趋化因子的产生。TGF-β和激活素信号通路在哮喘中的过敏原激发后被激活。激活素A可能有助于炎症的消退。
Both transforming growth factor (TGF)-β1 and activin-A have been implicated in airway remodelling in asthma but the modulation of their specific signalling pathways after disease activation remains undefined. To define the expression kinetics of TGF-β1, activin-A ligands and follistatin (a natural activin inhibitor), their Type I and Type II receptors (ALK-1, ALK-5 and ALK-4 and TβRII and ActRIIA/RIIB) and activation of signalling (via pSmad2), in the asthmatic airway following allergen challenge. Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic asthmatics (median age 25 years, median FEV1% predicted 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated using cultured normal human bronchial epithelial (NHBE) cells. pSmad2+ epithelial cells increased at 24 hours (p=0.03) and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin or TGF-β1 expression was demonstrated. Activin receptor+ cells increased after allergen challenge.: ALK-4 in epithelium (p=0.04) and submucosa (p=0.04), and ActRIIA in epithelium (p=0.01). The TGF-β receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was down-regulated in the epithelium after challenge (p=0.02), whereas ALK-1 and TβRII expression in the submucosa increased after allergen challenge (p=0.03 and p=0.004 respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-α, and down-regulated TNF-α and IL-13-induced chemokine production by NHBE cells. Both TGF-β and activin signalling pathways are activated upon allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.