Airway reactivity and sphingolipids-implications for childhood asthma.
Airway reactivity and sphingolipids-implications for childhood asthma.
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DOI：
10.1186/s40348-015-0025-3
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Worgall S
中科院分区：
文献类型：
--
作者：
Ono JG;Worgall TS;Worgall S
哮喘是一种临床异质性疾病，其发生和发展是遗传易感性、过敏原和病毒触发因素之间复杂相互作用的结果。鞘脂和鞘脂代谢改变已成为哮喘发病的潜在关键因素。ORMDL3基因和哮喘易感基因17q21与儿童哮喘密切相关，但该基因如何在功能上与哮喘相关尚不完全清楚。ORMDL蛋白在鞘磷脂的动态平衡和合成中起着不可或缺的作用，哮喘相关的ORMDL3基因多态性与早期病毒呼吸道感染和哮喘风险增加有关。ORMDL蛋白作为丝氨酸棕榈酰辅酶A转移酶(SPT)的抑制剂，SPT是神经鞘脂脂从头合成的限速酶，通过SPT减少神经鞘脂脂的合成增加了气道的高反应性，这与过敏或炎症无关。在哮喘的过敏性模型中，鞘氨醇介质1-磷酸鞘氨醇(S1P)和神经酰胺被证明是呼吸道高反应性、肥大细胞激活和炎症的重要信号分子。这篇综述将强调鞘脂和改变的鞘脂代谢如何有助于儿童哮喘的潜在机制。
Asthma is a clinically heterogeneous disorder, whose onset and progression results from a complex interplay between genetic susceptibility, allergens, and viral triggers. Sphingolipids and altered sphingolipid metabolism have emerged as potential key contributors to the pathogenesis of asthma. Orosomucoid-like 3 gene (ORMDL3) and the asthma susceptibility locus 17q21 have been strongly and reproducibly linked to childhood asthma, but how this gene is functionally linked to asthma is incompletely understood. ORMDL proteins play an integral role in sphingolipid homeostasis and synthesis, and asthma-associated ORMDL3 polymorphisms have been associated with early viral respiratory infections and increased risk of asthma. ORMDL proteins act as inhibitors of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis, and decreased sphingolipid synthesis through SPT increases airway hyperreactivity, which is independent of allergy or inflammation. In allergic models of asthma, the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide have been shown to be important signaling molecules for airway hyperreactivity, mast cell activation, and inflammation. This review will highlight how sphingolipids and altered sphingolipid metabolism may contribute towards the underlying mechanisms of childhood asthma.