A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma.
A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma.
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DOI：
10.1016/j.jaci.2012.07.014
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发表时间：
2013-02
影响因子：
14.2
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Price, Megan M.;Oskeritzian, Carole A.;Falanga, Yves T.;Harikumar, Kuzhuvelil B.;Allegood, Jeremy C.;Alvarez, Sergio E.;Conrad, Daniel;Ryan, John J.;Milstien, Sheldon;Spiegel, Sarah
关键词：
由两种鞘氨醇激酶同工酶SphK 1和SphK 2产生的鞘氨醇-1-磷酸（S1 P）与IgE介导的肥大细胞反应有关。然而，同种型特异性SphK基因敲除小鼠的过敏性炎症研究尚未阐明其贡献，S1 P在肥大细胞和IgE依赖性过敏性哮喘小鼠模型中的体内作用尚未得到研究。我们使用同工酶特异性SphK 1抑制剂SK 1-I，研究S1 P和SphK 1在小鼠肥大细胞依赖性气道高反应性（AHR）和气道炎症中的作用。在卵清蛋白（OVA）诱导的哮喘的肥大细胞依赖性小鼠模型中检测过敏性气道炎症和AHR。C57 BL/6小鼠在致敏和用OVA攻击之前或仅在攻击之前接受SK 1-I的鼻内递送。SK 1-I抑制人和鼠肥大细胞的抗原依赖性活化，并抑制NF-κB（一种调节促炎细胞因子表达的主转录因子）的活化。在没有佐剂的情况下，SK 1-I治疗对OVA致敏的小鼠，其发展肥大细胞依赖性过敏性炎症，显著降低了OVA诱导的乙酰甲胆碱AHR;降低了支气管肺泡灌洗液中嗜酸性粒细胞的数量和细胞因子IL-4、5、6、13、IFN-γ和TNF-α以及趋化因子eotaxin和CCL 2的水平;降低肺炎症反应及肺内NF-κB活化。S1 P和SphK 1在肥大细胞依赖性、OVA诱导的过敏性炎症和AHR中发挥重要作用，部分通过调节NF-κB通路。
Sphingosine-1-phosphate (S1P) produced by two sphingosine kinase isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype-specific SphK knockout mice have not clarified their contribution and the role that S1P plays in vivo in a mast cell and IgE-dependent mouse model of allergic asthma has not yet been examined. We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell dependent airway hyperresponsiveness (AHR) and airway inflammation in mice. Allergic airway inflammation and AHR were examined in a mast cell-dependent mouse model of ovalbumin (OVA)-induced asthma. C57BL/6 mice received intranasal delivery of SK1-I prior to sensitization and challenge with OVA or only prior to challenge. SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of NF-κB, a master transcription factor that regulates expression of pro-inflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, which develop mast cell-dependent allergic inflammation, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, 5, 6, 13, IFN-γ, and TNF-α and the chemokines eotaxin, and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation as well as activation of NF-κB in the lungs. S1P and SphK1 play important roles in mast cell-dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-κB pathway.
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脂质介质鞘氨醇1-磷酸在肥大细胞效应子功能和过敏性疾病中的新兴作用。
影响因子：
--
作者：
Olivera, Ana;Rivera, Juan
通讯作者：
Rivera, Juan
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
4.4
作者：
Gomez, G;Gonzalez-Espinosa, C;Rivera, J
通讯作者：
Rivera, J
影响因子：
14.2
作者：
Nakae, Susumu;Lunderius, Carolina;Galli, Stephen J.
通讯作者：
Galli, Stephen J.
哮喘治疗的一个潜在新目标：解整合素和金属蛋白酶 10 (ADAM10) 参与小鼠实验性哮喘。
影响因子：
12.4
作者：
Mathews JA;Ford J;Norton S;Kang D;Dellinger A;Gibb DR;Ford AQ;Massay H;Kepley CL;Scherle P;Keegan AD;Conrad DH
通讯作者：
Conrad DH