Kariyawasam Harsha H, Pegorier Sophie, Barkans Julia, Xanthou Georgina, Aizen Maxine, Ying Sun, Kay A Barry, Lloyd Clare M, Robinson Douglas S
Allergy and Clinical Immunology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
J Allergy Clin Immunol. 2009 Sep;124(3):454-62. doi: 10.1016/j.jaci.2009.06.022.
Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined.
To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge.
Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated by using cultured normal human bronchial epithelial (NHBE) cells.
pSmad2(+) epithelial cells increased at 24 hours (P = .03), and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin, or TGF-beta(1) expression was demonstrated. Activin receptor(+) cells increased after allergen challenge: ALK-4 in epithelium (P = .04) and submucosa (P = .04), and ActRIIA in epithelium (P = .01). The TGF-beta receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was downregulated in the epithelium after challenge (P = .02), whereas ALK-1 and TbetaRII expression in the submucosa increased after allergen challenge (P = .03 and P = .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-alpha, and downregulated TNF-alpha and IL-13-induced chemokine production by NHBE cells.
Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.
转化生长因子（TGF）-β1和激活素A均与哮喘气道重塑有关，但疾病激活后其特定信号通路的调节仍不明确。
明确变应原激发后哮喘气道中TGF-β1、激活素A配体和卵泡抑素（一种天然激活素抑制剂）及其I型和II型受体（激活素样激酶[ALK]-1、ALK-5、ALK-4、TβRII和ActRIIA/RIIB）的表达动力学以及信号传导的激活（通过磷酸化（p）Smad2）情况。
对15例轻度特应性哮喘患者（中位年龄25岁；预计FEV1%中位值为97%）的支气管活检标本在基线时以及变应原吸入后24小时进行免疫组织化学检测。通过培养的正常人支气管上皮（NHBE）细胞评估激活素A的功能效应。
pSmad2阳性上皮细胞在吸入变应原24小时时增加（P = 0.03），且在黏膜下细胞中检测到pSmad2。未发现激活素A、卵泡抑素或TGF-β1表达的调节变化。变应原激发后激活素受体阳性细胞增加：上皮中的ALK-4（P = 0.04）和黏膜下中的ALK-4（P = 0.04），以及上皮中的ActRIIA（P = 0.01）。TGF-β受体ALK-5在基线和激发后黏膜下的表达极少，激发后上皮中的表达下调（P = 0.02），而变应原激发后黏膜下的ALK-1和TβRII表达增加（分别为P = 0.03和P = 0.004）。变应原激发后T细胞中ALK-1和ALK-4的表达增加。激活素A诱导NHBE细胞增殖，由NHBE细胞对TNF-α产生反应而分泌，并下调TNF-α和IL-13诱导的NHBE细胞趋化因子产生。
哮喘中变应原激发可激活TGF-β和激活素信号通路。激活素A可能有助于炎症的消退。
