Mechanisms of BDNF regulation in asthmatic airway smooth muscle
Mechanisms of BDNF regulation in asthmatic airway smooth muscle
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DOI：
10.1152/ajplung.00414.2015
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发表时间：
2016-08-01
影响因子：
4.9
通讯作者：
Prakash, Y. S.
中科院分区：
文献类型：
--
作者：
Aravamudan, Bharathi;Thompson, Michael A.;Prakash, Y. S.
脑源性神经营养因子（BDNF）是一种由气道平滑肌（ASM）产生的神经营养因子，增强炎症对气道收缩性的影响，支持局部产生的生长因子影响气道疾病（如哮喘）的观点。本研究旨在探讨调节内源性及炎症（TNF-α）诱导的非哮喘与哮喘人ASM中BDNF分泌的内在机制。我们专注于特定的Ca 2+调节和炎症相关的信号级联和定量BDNF分泌。我们发现TNF-α通过几种与哮喘相关的机制增强ASM细胞的BDNF释放，包括瞬时受体电位通道TRPC 3和TRPC 6（但不包括TRPC 1）、ERK 1/2、PI 3 K、PLC和PKC级联、Rho激酶以及转录因子cAMP反应元件结合蛋白和活化T细胞的核因子。哮喘ASM中基础BDNF表达和分泌升高，并随着TNF-α暴露进一步增加，涉及许多这些调节机制。我们的结论是，气道BDNF的分泌在多个层面上进行调节，提供了一个基础的自分泌作用的BDNF炎症和疾病的条件下，与潜在的下游影响收缩和重塑。
Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-alpha)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca2+ regulation and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-alpha enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-alpha exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling.