哮喘中气道重塑及炎症依赖于细胞外基质蛋白fibulin-1c

2017/12/20

   摘要
   哮喘是一种慢性气道炎症性疾病,以变应性气到炎症、气道重塑及气道高反应为特征。哮喘患者,尤其是伴有慢性或重度哮喘的患者,气到重塑与细胞外基质蛋白聚积有关,如胶原蛋白。Fibulin-1 (Fbln1)是一种重要的基质蛋白,它气到了稳定胶原蛋白及其他基质蛋白的作用。Fbln1有四种异构体,其中Fbln1c是人与小鼠中的主要表达种类。在尘螨诱导的慢性过敏性气道疾病小鼠模型中,肺脏组织中Fbln1c表达增高。在过敏性气道疾病小鼠模型中,基因敲除、治疗抑制Fbln1c后,气道胶原沉积减少,气道高反应减弱。与野生型小鼠相比,Fbln1c缺陷组中,黏液蛋白MUC5AC表达水平降低,但MUC5B表达水平无明显差异。骨膜蛋白是一种分布在小气道周围链接胶原蛋白的蛋白,Fbln1c在这种链接中起到了介导作用。与野生型小鼠相比,Fbln1c缺陷过敏性气道疾病小鼠模型中,气道周围α平滑肌肌动蛋白阳性细胞的数量减少,气道收缩性降低。尘螨处理后,小鼠气道炎症细胞减少,肺组织中IL-5、IL-13、IL-33、TNF以及CXCL1表达降低,肺部淋巴结中IL-5、IL-33以及TNF表达降低。长时间尘螨处理及Fbln1c治疗处理后的小鼠的肺脏及淋巴结中,GATA3阳性Th2细胞数量减少。处理后的混合培养树突状细胞和T细胞中,IL-5和IL-13分泌减少。添加Fbln1c培养的的人上皮细胞CXCL1 mRNA表达较正常培养的细胞中表达增高。我们的数据显示,Fbln1c可能是慢性哮喘的一个治疗靶点。

 
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Pathol. 2017 Dec;243(4):510-523.)


 
 
 
Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.
 
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, Haw TJ, Hansbro NG, Ge Q, Brown AC, Tay H, Foster PS, Wark PA, Horvat JC, Bourke JE, Grainge CL, Argraves WS, Oliver BG, Knight DA, Burgess JK, Hansbro PM.
 
Abstract
Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c -/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c -/-mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland.


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