Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca(2+) oscillations in asthma.
Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca(2+) oscillations in asthma.
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DOI：
10.1016/j.jaci.2017.08.015
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Broide DH
中科院分区：
文献类型：
--
作者：
Chen J;Miller M;Unno H;Rosenthal P;Sanderson MJ;Broide DH
气道高反应性（AHR）是哮喘的主要特征，主要归因于增加气道平滑肌（ASM）收缩性的外源性免疫/炎症反应。我们研究了染色体17 q21上与哮喘高度相关的基因ORMDL 3的ASM表达增加是否在体外诱导ASM增殖和收缩性增加，以及影响WT和hORMDL 3 Zp 3-Cre小鼠（其表达增加水平的人ORMDL 3）的精密切割肺切片中ASM中的气道收缩性和钙通量。在体外用ORMDL 3转染的ASM细胞中评估ASM增殖和收缩的水平。此外，在源自未处理WT和未处理hORMDL 3 Zp 3-Cre小鼠的精确切割肺切片中的ASM细胞中定量气道收缩性和钙波动，所述小鼠没有血液供应。在体外增加的ASM表达ORMDL 3导致增加的ASM增殖和收缩性。源自未发生气道炎症的未处理hORMDL 3 Zp 3-Cre小鼠的精密切割肺切片显示气道收缩性增加，ASM细胞中钙振荡增加。增加的ASM ORMDL 3增加ASM肌浆网Ca 2 + ATP酶2b（SERCA 2b），其增加ASM增殖和收缩性。总体而言，这些研究提供了证据，表明ASM中ORMDL 3的内在增加可诱导ASM增殖和收缩性增加，这可能有助于在哮喘中不存在气道炎症的情况下增加AHR。
Airway hyperresponsiveness (AHR) is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. We investigated whether increased ASM expression of ORMDL3, a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro, as well as influenced airway contractility and calcium flux in ASM in precision cut lung slices from WT and hORMDL3Zp3-Cre mice (which express increased levels of human ORMDL3). Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in precision cut lung slices derived from naïve WT and naïve hORMDL3Zp3-Cre mice which do not have a blood supply. Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. Precision cut lung slices derived from naïve hORMDL3Zp3-Cre mice which do not have airway inflammation exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 increases ASM sarcoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) which increases ASM proliferation and contractility. Overall, these studies provide evidence that an intrinsic increase in ORMDL3 in ASM can induce increased ASM proliferation and contractility which may contribute to increased AHR in the absence of airway inflammation in asthma.
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DOI：
10.4049/jimmunol.1601848
发表时间：
2017-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
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
通讯作者：
Broide DH
DOI：
10.1164/ajrccm/141.5_pt_1.1327
发表时间：
1990-05-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
EBINA, M;YAEGASHI, H;TANEMURA, M
通讯作者：
TANEMURA, M
影响因子：
9.6
作者：
Busse, William W.
通讯作者：
Busse, William W.
ORM家族蛋白介导鞘脂稳态。
影响因子：
64.8
作者：
Breslow, David K.;Collins, Sean R.;Bodenmiller, Bernd;Aebersold, Ruedi;Simons, Kai;Shevchenko, Andrej;Ejsing, Christer S.;Weissman, Jonathan S.
通讯作者：
Weissman, Jonathan S.
影响因子：
4
作者：
Lauzon AM;Bates JH;Donovan G;Tawhai M;Sneyd J;Sanderson MJ
通讯作者：
Sanderson MJ