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首页> 外文期刊>Allergy >Targeting PP PP 2A and proteasome activity ameliorates features of allergic airway disease in mice
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Targeting PP PP 2A and proteasome activity ameliorates features of allergic airway disease in mice

机译：靶向PP PP 2A和蛋白酶体活性改善小鼠过敏气道病的特征

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摘要

Abstract Background Asthma is an allergic airway disease ( AAD ) caused by aberrant immune responses to allergens. Protein phosphatase‐2A ( PP 2A) is an abundant serine/threonine phosphatase with anti‐inflammatory activity. The ubiquitin proteasome system ( UPS ) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP 2A activity with fingolimod ( FTY 720) or 2‐amino‐4‐(4‐(heptyloxy) phenyl)‐2‐methylbutan‐1‐ol ( AAL (S) ), or inhibiting proteasome activity with bortezomib ( BORT ), could suppress experimental AAD . Methods Acute AAD was induced in C57 BL /6 mice by intraperitoneal sensitization with ovalbumin ( OVA ) in combination with intranasal (i.n) exposure to OVA . Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite ( HDM ) extract. Mice were treated with vehicle, FTY 720, AAL (S) , BORT or AAL (S) + BORT and hallmark features of AAD assessed. Results AAL (S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus‐secreting cell ( MSC ) numbers, type 2‐associated cytokines (interleukin ( IL )‐33, thymic stromal lymphopoietin, IL ‐5 and IL ‐13), serum immunoglobulin (Ig)E and airway hyper‐responsiveness ( AHR ). FTY 720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid ( BALF ) and tissue eosinophils and inflammation, IL ‐5, IL ‐13 and AHR . Combined treatment with AAL (S) + BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type 2 cytokines and AHR . AAL (S) , BORT and AAL (S) + BORT also reduced airway remodelling in chronic AAD . Conclusion These findings highlight the potential of combination therapies that enhance PP 2A and inhibit proteasome activity as novel therapeutic strategies for asthma.
机译：摘要背景哮喘是一种过敏气道疾病（AAD）由异常免疫反应引起的过敏原。蛋白质磷酸酶-2a（pp 2a）是具有抗炎活性的丰富丝氨酸/苏氨酸磷酸酶。泛素蛋白酶体系（UPS）控制许多细胞过程，包括通过蛋白质降解引发炎症反应。我们评估了用Fingolimod（FTY 720）或2-氨基-4-（4-（庚氧基）苯基）-2-甲基丁丹-1-醇（aal（s））的pp 2a活性，或抑制蛋白酶体活性与bortezomib（ BORT），可以抑制实验AAD。方法通过腹膜内敏化（OVA）与鼻内（I.n）暴露于OVA，通过腹膜内敏化诱导急性AAD在C57 BL / 6小鼠中诱导。慢性AAD在小鼠中诱导，延长I.N暴露于粗屋粉尘螨（HDM）提取物。通过载体，FTY 720，AAL（S），Bort或AA1（S）+ Bort和Hallmark特征进行评估，对小鼠进行处理。结果aal（s）通过抑制组织嗜酸性粒细胞和炎症，粘液分泌细胞（MSC）数，2型相关细胞因子（白细胞介素（IL）-33，胸腺基质淋巴二胞苷，IL-5和IL来降低急性AAD的严重程度13），血清免疫球蛋白（IG）E和Airway超响应性（AHR）。 FTY 720只抑制了组织炎症和IgE。 DORT降至支气管肺泡灌洗液（BALF）和组织嗜酸性粒细胞和炎症，IL -5，IL -13和AHR。使用AAL（S）+ BOROR的组合治疗具有互补效果和抑制BALF和组织嗜酸性粒细胞和炎症，MSC编号，减少了2型细胞因子和AHR的产生。 aal（s），bort和aal（s）+ dort在慢性AAD中还减少了气道重塑。结论这些发现突出了增强PP 2A的组合疗法的潜力，并抑制蛋白酶体活性作为哮喘的新疗法策略。

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  • 来源
    《Allergy》 |2017年第12期|共13页
  • 作者

    Nair P. M.; Starkey M. R.; Haw T. J.; Liu G.; Horvat J. C.; Morris J. C.; Verrills N. M.; Clark A. R.; Ammit A. J.; Hansbro P. M.;

  • 作者单位

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    School of ChemistryUniversity of New South WalesSydney NSW Australia;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

    Institute of Inflammation and AgeingUniversity of BirminghamBirmingham UK;

    Woolcock Emphysema CentreUniversity of SydneySydney NSW Australia;

    Priority Research Centres for Healthy LungsUniversity of Newcastle &

    Hunter Medical Research;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

    allergic airway disease; asthma; inflammation; protein phosphatase 2A; ubiquitin proteasome system;

    机译：过敏气道病;哮喘;炎症;蛋白质磷酸酶2a;泛素蛋白酶体系;

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