ADSC外泌体通过MTI抑制染尘巨噬细胞NIK/IKKα/P100信号通路治疗矽肺的实验研究

染尘巨噬细胞炎症反应是矽肺发病的重要环节。脂肪干细胞（ADSC）外泌体可以抑制巨噬细胞炎症反应，但能否抑制染尘巨噬细胞炎症反应尚不清楚。我们最近发现ADSC外泌体中金属硫蛋白(MTI)表达显著抑制染尘巨噬细胞中NF-κB诱导激酶(NIK)蛋白表达，并下调NF-κB抑制蛋白激酶α(IKKα)和NF-κBp52蛋白表达。鉴于NIK和IKKα在NIK/IKKα/P100通路激活NF-κB2中起重要作用，我们推测ADSC外泌体中MTI可能通过抑制染尘巨噬细胞中NIK/IKKα/P100通路介导的NF-κB2激活发挥抗炎作用。本项目拟利用蛋白质组学分析数据，从矽肺小鼠模型、细胞与分子水平明确ADSC外泌体抑制矽肺炎症反应的作用；阐明MTI抑制NIK/IKKα/P100通路介导的NF-κB2激活在染尘巨噬细胞抗炎反应中的具体机制。本研究将为探索ADSC外泌体治疗矽肺奠定理论基础。

Inflammatory response of dust-exposed macrophages plays an important role in the pathogenesis of silicosis. The exosomes of adipose stem cell (ADSC) involves in the inflammation of macrophage, but ADSC inhibits the inflammatory response of dust-exposed macrophages remains unclear. Recently, our preliminary experiments documented the expression of metallothionein (MTI) in ADSC exosomes significantly inhibited the expression of NF-kappa B-induced kinase (NIK) in dust-exposed macrophages, and inhibited the expression of protein kinase alpha (IKKα) and NF-kB p52. We put forward the scientific hypothesis that ADSC exosomes could play an anti-inflammatory role by inhibiting the activation of NF-kB2 by MTI via NIK/IKKα/P100 pathway in dust-exposed macrophages. On the proteomic analysis data bases, the dust-exposed macrophages and silicosis mice models will be used to investigate the underlining mechanisms of NIK/IKKα/P100 pathway in inhibiting the activation of NF-kB2 both in vivo and in vitro. In the meantime, we will comprehensively analyze the role of ADSC exosome in inhibiting inflammatory response of silicosis. Above all, this study will provide new anti-inflammation method and theoretical basis for the treatment of silicosis.