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.

中文翻译：

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气道反应性和鞘脂——对儿童哮喘的影响

哮喘是一种临床异质性疾病，其发病和进展是遗传易感性、过敏原和病毒触发因素之间复杂相互作用的结果。鞘脂和改变的鞘脂代谢已成为哮喘发病机制的潜在关键因素。Orosomucoid-like 3 基因 (ORMDL3) 和哮喘易感基因座 17q21 与儿童哮喘密切相关且可重复，但该基因如何在功能上与哮喘相关尚不完全清楚。ORMDL 蛋白在鞘脂稳态和合成中起着不可或缺的作用，哮喘相关的 ORMDL3 多态性与早期病毒性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，鞘脂从头合成的限速酶和通过 SPT 减少鞘脂合成会增加气道高反应性，这与过敏或炎症无关。在哮喘的过敏模型中，鞘脂介质 1-磷酸鞘氨醇 (S1P) 和神经酰胺已被证明是气道高反应性、肥大细胞活化和炎症的重要信号分子。本综述将重点介绍鞘脂和改变的鞘脂代谢如何促进儿童哮喘的潜在机制。鞘脂介质 1-磷酸鞘氨醇 (S1P) 和神经酰胺已被证明是气道高反应性、肥大细胞活化和炎症的重要信号分子。本综述将重点介绍鞘脂和改变的鞘脂代谢如何促进儿童哮喘的潜在机制。鞘脂介质 1-磷酸鞘氨醇 (S1P) 和神经酰胺已被证明是气道高反应性、肥大细胞活化和炎症的重要信号分子。本综述将重点介绍鞘脂和改变的鞘脂代谢如何促进儿童哮喘的潜在机制。