Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma
Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma
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DOI：
10.1152/ajplung.00575.2016
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发表时间：
2018-01-01
影响因子：
4.9
通讯作者：
Sakai, Hiroyasu
中科院分区：
文献类型：
--
作者：
Chiba, Yoshihiko;Danno, Shunta;Sakai, Hiroyasu
前颗粒蛋白（PGRN）是一种具有多种生物学功能的生长因子，已被认为是肿瘤坏死因子- α (tnf - α)介导的信号传导的内源性抑制剂。tnf - α被认为是哮喘发病机制的重要介质之一，包括气道高反应性（AHR）。本研究在体外和体内研究了重组PGRN对支气管平滑肌（bsm）中tnf - α介导的信号传导和抗原诱导的过度收缩的影响。采用培养的人BSM细胞（hBSMCs）和雄性BALB/c小鼠。小鼠被致敏并反复用卵清蛋白抗原刺激。在每次吸入抗原前1小时，将重组PGRN鼻内注入气道。在hBSMCs中，PGRN抑制了tnf - α诱导的I κ B- α的降解（nf - κ B激活的指标）和RhoA（一种收缩机械相关蛋白，有助于BSM高反应性）的上调，表明PGRN在BSM细胞中也具有抑制tnf - α介导的信号传导的能力。在反复抗原刺激小鼠的bsm中，观察到对乙酰胆碱的收缩反应增强，RhoA上调：这两种事件都通过鼻内PGRN预处理得到改善。有趣的是，与对照动物相比，反复抗原刺激小鼠气道中PGRN表达显著下降。综上所述，外源性PGRN进入气道改善了抗原诱导的BSM高反应性，可能是通过阻断tnf - α介导的反应。提高PGRN水平可能是治疗过敏性哮喘AHR的一种有希望的方法。
Progranulin (PGRN) is a growth factor with multiple biological functions and has been suggested as an endogenous inhibitor of Tumor necrosis factor-alpha (TNF-alpha)-mediated signaling. TNF-alpha is believed to be one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on TNF-alpha-mediated signaling and antigen-induced hypercontractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used. The mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also received intranasal administrations of recombinant PGRN into the airways 1 h before each antigen inhalation. In hBSMCs, PGRN inhibited both the degradation of I kappa B-alpha (an index of NF-kappa B activation) and the upregulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNF-alpha, indicating that PGRN has an ability to inhibit TNF-alpha -mediated signaling also in the BSM cells. In BSMs of the repeatedly antigen-challenged mice, an augmented contractile responsiveness to acetylcholine with an upregulation of RhoA was observed: both the events were ameliorated by pretreatments with PGRN intranasally. Interestingly, a significant decrease in PGRN expression was found in the airways of the repeatedly antigen-challenged mice rather than those of control animals. In conclusion, exogenously applied PGRN into the airways ameliorated the antigen-induced BSM hyperresponsiveness, probably by blocking TNF-alpha -mediated response. Increasing PGRN levels might be a promising therapeutic for AHR in allergic asthma.