气道黏膜屏障中硫酸乙酰肝素的硫酸化修饰：过敏性呼吸系统疾病中的生物合成调控、病理意义及治疗靶点

文献信息

中文摘要

硫酸乙酰肝素（HS）是一种高度硫酸化的糖胺聚糖，对气道黏膜屏障功能至关重要。其生物活性由通过N-脱乙酰酶/N-磺基转移酶（NDST1-4）和O-磺基转移酶生成的“硫酸化密码”决定。新出现的证据表明，HS硫酸化在一个狭窄的稳态范围内运作——一种“变阻器”——硫酸化不足和过度都会破坏屏障完整性并促进炎症。本综述提出HS硫酸化变阻器模型，作为过敏性呼吸系统疾病的统一框架。我们审视HS生物合成机制及其在转录、表观遗传和代谢水平的调控，重点强调组蛋白乳酰化作为HS酶表达的代谢-表观遗传变阻器。我们总结HS在稳态范围内的功能，包括糖萼完整性、紧密连接调控和生长因子信号传导。随后我们讨论过敏性气道炎症中的变阻器失调，重点关注来自NDST1缺陷小鼠的证据，这些证据表明HS N-硫酸化介导嗜酸性粒细胞募集、趋化因子隔离和气道重塑。评估了关键争议，包括NDST1与NDST3之争、细胞类型特异性功能以及转化差距。最后，我们强调恢复变阻器的治疗策略，包括非抗凝肝素衍生物、确定的HS寡糖、乙酰肝素酶抑制剂和HS拟糖物。理解HS硫酸化变阻器及其通过糖表观遗传轴的调控，可能为过敏性鼻炎、哮喘及相关气道疾病确定新的治疗靶点。全文强调区室特异性设定点：上皮硫酸化增强屏障完整性，而内皮和白细胞硫酸化则调控白细胞募集和趋化因子呈递。

英文摘要

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan essential for airway mucosal barrier function. Its biological activities are determined by the "sulfation code" generated through N-deacetylase/N-sulfotransferases (NDST1-4) and O-sulfotransferases. Emerging evidence indicates that HS sulfation operates within a narrow homeostatic range - a "rheostat" - where both insufficient and excessive sulfation disrupt barrier integrity and promote inflammation. This review proposes the HS sulfation rheostat model as a unifying framework for allergic respiratory diseases. We examine the HS biosynthetic machinery and its regulation at transcriptional, epigenetic, and metabolic levels, with emphasis on histone lactylation as a metabolic-epigenetic rheostat for HS enzyme expression. We summarize HS functions within the homeostatic range, including glycocalyx integrity, tight junction regulation, and growth factor signaling. We then discuss rheostat dysregulation in allergic airway inflammation, focusing on evidence from NDST1-deficient mice demonstrating that HS N-sulfation mediates eosinophil recruitment, chemokine sequestration, and airway remodelling. Key controversies are appraised, including the NDST1 versus NDST3 debate, cell-type-specific functions, and the translational gap. Finally, we highlight therapeutic strategies for restoring the rheostat, including non-anticoagulant heparin derivatives, defined HS oligosaccharides, heparanase inhibitors, and HS glycomimetics. Understanding the HS sulfation rheostat and its regulation through the glycoepigenetics axis may identify new therapeutic targets for allergic rhinitis, asthma, and related airway diseases. Compartment-specific set points are emphasized throughout: epithelial sulfation reinforces barrier integrity, whereas endothelial and leukocyte sulfation governs leukocyte recruitment and chemokine presentation.