Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.

鞘脂合成受损在遗传上与儿童哮喘有关，在功能上与气道高反应性 (AHR) 相关。目的是研究鞘脂合成是否可以成为哮喘治疗的目标。在缺乏 SPT（丝氨酸棕榈酰辅酶 A 转移酶）（鞘脂合成的限速酶）的小鼠中评估了 GlyH-101 和芬维A胺通过调节从头鞘脂合成对 AHR 的影响。这些药物还直接用于人类气道平滑肌和上皮细胞，以评估从头鞘脂代谢物和钙释放的变化。GlyH-101 和芬维A胺增加了鞘氨醇和二氢神经酰胺（从头鞘脂代谢物）在肺上皮和气道平滑肌细胞中，降低气道平滑肌细胞中的细胞内钙浓度，并减少激动剂诱导的近端和外周气道收缩。GlyH-101 还降低了体内SPT 缺陷小鼠的 AHR 。该研究将鞘脂合成的操作确定为减轻 AHR 的新型代谢治疗策略。