The role of sphingosine kinase in a murine model of allergic asthma
The role of sphingosine kinase in a murine model of allergic asthma
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DOI：
10.4049/jimmunol.180.6.4323
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发表时间：
2008-03-15
影响因子：
4.4
通讯作者：
Leung, Bernard P.
中科院分区：
文献类型：
--
作者：
Lai, Wen-Qi;Goh, Hong Heng;Leung, Bernard P.
哮喘是一种过敏性疾病，以慢性呼吸道嗜酸性粒细胞增多和肺内淋巴细胞，特别是Th2亚型、巨噬细胞和肥大细胞的浸润为特征。以往的研究表明，鞘氨酸激酶(SphK)在多种促炎细胞中起着关键作用，如淋巴细胞和嗜酸性粒细胞迁移和肥大细胞脱颗粒。因此，我们研究了SphK在过敏性哮喘小鼠模型中的作用。在先前对OVA致敏的小鼠中，ip。吸入OVA后，给予有效的SphK抑制剂NN二甲基鞘氨醇(DMS)可显著降低肺泡灌洗液中炎症细胞的渗出和嗜酸性粒细胞的增多以及IL-4、IL-5和嗜酸性粒细胞趋化因子的水平。此外，DMS以剂量依赖的方式显著抑制OVA诱导的肺部炎症浸润和粘液产生，以及对乙酰甲胆碱的高反应性。DMS处理的小鼠胸腺淋巴结培养中，OVA诱导的淋巴细胞增殖和IL-4、IL-5分泌减少。此外，通过小干扰RNA方法，SphK1基因敲除的小鼠在炎症浸润物、支气管肺泡灌洗、IL-4、IL-5、嗜酸性粒细胞趋化因子和血清OVA特异性IgE水平方面也观察到类似的减少。综上所述，这些数据证明了SphK调制在过敏性呼吸道疾病中的治疗潜力。
Asthma is an allergic disease characterized by chronic airway eosinophilia and pulmonary infiltration of lymphocytes, particularly of the Th2 subtype, macrophages and mast cells. Previous studies have shown a pivotal role for sphingosine kinase (SphK) on various proinflammatory cells, such as lymphocyte and eosinophil migration and mast cell degranulation. We therefore examined the roles of SphK in a murine model of allergic asthma. In mice previously sensitized to OVA, i.p. administration of NNdimethylsphingosine (DMS), a potent SphK inhibitor, significantly reduced the total inflammatory cell infiltrate and eosinophilia and the IL-4, IL-5, and eotaxin levels in bronchoalveolar lavage fluid in response to inhaled OVA challenge. In addition, DMS significantly suppressed OVA-induced inflammatory infiltrates and mucus production in the lungs, and airway hyperresponsiveness to methacholine in a dose-dependent manner. OVA-induced lymphocyte proliferation and IL-4 and IL-5 secretion were reduced in thoracic lymph node cultures from DMS-treated mice. Moreover, similar reduction in inflammatory infiltrates, bronchoalveolar lavage, IL-4, IL-5, eotaxin, and serum OVA-specific IgE levels was observed in mice with SphK1 knock-down via small interfering RNA approach. Together, these data demonstrate the therapeutic potential of SphK modulation in allergic airways disease.