Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model
Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model
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DOI：
10.1165/rcmb.2014-0231oc
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发表时间：
2015-09-01
影响因子：
6.4
通讯作者：
Walker, Julia K. L.
中科院分区：
文献类型：
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作者：
Chen, Minyong;Hegde, Akhil;Walker, Julia K. L.
beta-Arrestin-2 (beta arr2) 是一种普遍表达的胞质蛋白，可终止 G 蛋白偶联受体信号传导并转导不依赖于 G 蛋白的信号传导。我们之前表明，缺乏 beta arr2 的小鼠在对过敏原敏感或受到过敏原攻击时不会出现哮喘表型。目前的研究评估是否可以通过使用诱导型 Cre 重组酶删除 beta arr2 来减轻已确定的哮喘表型。我们对小鼠进行卵清蛋白 (OVA) 致敏和攻击，并证明在第 24 天 (d) 时，未诱导的 β arr2 和野生型 (WT) 小鼠中过敏性哮喘表型很明显。在第二组 OVA 处理的小鼠中，在第 24 天至第 28 天注射他莫昔芬以激活 Cre 重组酶，并持续进行 OVA 气雾攻击直至第 44 天。使用肺力学测量、支气管肺泡灌洗细胞分析以及粘蛋白和气道炎症的组织学评估来评估哮喘表型。与各自的盐水处理对照相比，OVA 处理的 WT 小鼠和表达诱导型 Cre 重组酶的小鼠在第 45 天表现出显着的哮喘表型。虽然他莫昔芬治疗对 WT 小鼠的哮喘表型没有显着影响，但它抑制了 β arr2 的表达，并导致 Cre 诱导小鼠的气道高反应性 (AHR) 显着降低。这些发现表明，β arr2 对于过敏性哮喘表型的 AHR 成分的永久存在是必需的。我们发现，β arr2 参与哮喘模型中 AHR 的持续存在，这意味着靶向 β arr2 可能会立即且可能长期缓解 AHR 引起的日常哮喘症状，而与炎症无关。
beta-Arrestin-2 (beta arr2) is a ubiquitously expressed cytosolic protein that terminates G protein-coupled receptor signaling and transduces G protein-independent signaling. We previously showed that mice lacking beta arr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of beta arr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced beta arr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited beta arr2 expression and caused a significant reduction in airway hyperresponsiveness (AHR) in Cre-inducible mice. These findings suggest that beta arr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that beta arr2 participates in the perpetuation of AHR in an asthma model means that targeting beta arr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation.