PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice
PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice
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PARP 在人类哮喘中被激活，奥拉帕尼对其的抑制可阻止房尘螨诱发的小鼠疾病
DOI：
10.1042/cs20150122
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发表时间：
2015-12-01
期刊：
影响因子：
6
通讯作者：
Boulares, A. Hamid
中科院分区：
文献类型：
--
作者：
Ghonim, Mohamed A.;Pyakurel, Kusma;Boulares, A. Hamid
我们的实验室确定了聚（ADP-核糖）聚合酶（PARP）在哮喘中的作用。为了提高我们研究的临床意义，必须证明 PARP 在人类哮喘中实际上被激活，检查批准用于人体测试的 PARP 抑制剂（如奥拉帕尼）是否会阻断小鼠体内对房尘螨（HDM）（一种真正的人类过敏原）反应的已确定的慢性哮喘特征，并检查该药物是否调节人类分化簇 4 型（CD4（+））T 细胞功能。为了进行这项研究，使用了人类肺标本和外周血单核细胞 (PBMC) 以及基于 HDM 的小鼠哮喘模型。我们的结果表明 PARP 在哮喘患者的 PBMC 和肺组织中被激活。奥拉帕尼或基因敲除对 PARP 的抑制可阻断长期暴露于 HDM 的小鼠中已建立的哮喘样特征，包括气道嗜酸性粒细胞增多和高反应性。这些影响与辅助性 T 细胞 2 (Th2) 细胞因子产生的显着减少有关，但对干扰素 (IFN)-γ 或白细胞介素 (IL)-10 没有显着影响。 PARP 抑制可阻止 HDM 诱导的处理小鼠脾脏中总体细胞结构、重量和 CD4(+) T 细胞数量的增加，同时增加 T 调节细胞数量。在 CD3/CD28 刺激的人 CD4(+) T 细胞中，奥拉帕尼治疗可能通过调节 GATA 结合蛋白-3 (gata-3)/IL-4 表达来减少 Th2 细胞因子的产生，同时适度影响 T 细胞增殖。 PARP 抑制不一致地增加 HDM 暴露小鼠和 CD3/CD28 刺激的 CD4(+) T 细胞中的 IL-17，但不会同时增加可能受 IL-17 影响的因子。在本研究中，我们首次提供证据表明 PARP-1 在人类哮喘中被激活，并且其抑制作用可有效阻止小鼠中已形成的哮喘。
Our laboratory established a role for poly(ADP-ribose) polymerase (PARP) in asthma. To increase the clinical significance of our studies, it is imperative to demonstrate that PARP is actually activated in human asthma, to examine whether a PARP inhibitor approved for human testing such as olaparib blocks already-established chronic asthma traits in response to house dust mite (HDM), a true human allergen, in mice and to examine whether the drug modulates human cluster of differentiation type 4 (CD4(+)) T-cell function. To conduct the study, human lung specimens and peripheral blood mononuclear cells (PBMCs) and a HDM-based mouse asthma model were used. Our results show that PARP is activated in PBMCs and lung tissues of asthmatics. PARP inhibition by olaparib or gene knockout blocked established asthma-like traits in mice chronically exposed to HDM including airway eosinophilia and hyper-responsiveness. These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-gamma or interleukin (IL)-10. PARP inhibition prevented HDM-induced increase in overall cellularity, weight and CD4(+) T-cell population in spleens of treated mice whereas it increased the T-regulatory cell population. In CD3/CD28-stimulated human CD4(+) T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 (gata-3)/IL-4 expression while moderately affecting T-cell proliferation. PARP inhibition inconsistently increased IL-17 in HDM-exposed mice and CD3/CD28-stimulated CD4(+) T cells without a concomitant increase in factors that can be influenced by IL-17. In the present study, we provide evidence for the first time that PARP-1 is activated in human asthma and that its inhibition is effective in blocking established asthma in mice.