Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.
Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.
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DOI：
10.4049/jimmunol.1601848
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发表时间：
2017-04-15
期刊：
影响因子：
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通讯作者：
Broide DH
中科院分区：
文献类型：
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作者：
Miller M;Tam AB;Mueller JL;Rosenthal P;Beppu A;Gordillo R;McGeough MD;Vuong C;Doherty TA;Hoffman HM;Niwa M;Broide DH
在这项研究中，我们使用cre-lox技术在呼吸道上皮细胞中产生选择性缺失ORMDL3的小鼠(ORMDL3Δ2-3/Δ2-3CC10)，以模拟一种有效抑制呼吸道中ORMDL3表达的吸入疗法。与预期的呼吸道反应性降低相反，卵清蛋白过敏原攻击的ORMDL3Δ2-3/Δ2-3CC10小鼠与野生型(WT)小鼠相比，气道反应性显著增加。ORMDL3Δ2-3/Δ2-3CC10和WT小鼠的气道炎症、黏液、纤维化和气道平滑肌水平无差异。但在ORMDL3Δ2-3/Δ2-3CC10小鼠中，1-磷酸鞘氨醇(S1P)的水平显著升高，而在用小干扰RNA抑制ORMDL3的呼吸道上皮细胞中，S1P的水平也显著升高。S1P与ASM细胞孵育可显著增强血管的收缩能力。总体而言，ORMDL3Δ2-3/Δ2-3CC10小鼠表现出变应原诱导的AHR增加，与炎症无关，并与S1P生成增加相关。这些研究引起了人们对吸入疗法的关注，这些疗法选择性和有效地抑制哮喘患者呼吸道上皮细胞中的ORMDL3。
In this study we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway responsiveness (AHR), OVA allergen challenged Ormdl3Δ2-3/Δ2-3CC10 mice had a significant increase in AHR compared to wild type (WT) mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle (ASM) were no different in Ormdl3Δ2-3/Δ2-3CC10 and WT mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with siRNA. Incubation of S1P with ASM cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3CC10 mice exhibit increased allergen induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.