精准医学时代的上皮屏障功能障碍与支气管哮喘的研究进展

Epithelial barrier dysfunction and bronchial asthma in the era of precision medicine: recent advances

摘要:

支气管哮喘是一种异质性显著的慢性呼吸道疾病，其发病率在全球范围内持续攀升。呼吸道上皮屏障的结构完整性和稳态维持对哮喘的发生、发展具有重要意义。上皮层集物理阻隔、免疫监视和抗氧化防御于一体，当紧密连接、黏附连接或桥粒受损时，可触发局部慢性炎症、微生物群失衡及气道重塑。遗传学和表观遗传学研究进一步揭示了原钙黏蛋白1、钙黏蛋白相关家族成员3等上皮高表达易感基因及DNA甲基化、组蛋白修饰和miRNA失调在哮喘易感性中的关键作用。临床T 2-high型和T 2-low型免疫表型均与上皮屏障功能障碍密切相关，但在炎症细胞谱系、药物反应与重塑模式上存在差异。靶向胸腺基质淋巴细胞生成素、白细胞介素（IL）-33、IL-4/IL-13及IL-5生物制剂可改善重症哮喘的症状控制和结构损伤；同时，组蛋白去乙酰化酶调节剂和基于miRNA的治疗策略等表观遗传疗法正展现出新的应用前景。未来通过整合遗传-表观遗传特征与屏障功能评估，可望实现更为精细的分型诊断和个体化干预，从而推动哮喘精准医学的持续发展。

Abstract:

Bronchial asthma is a highly heterogeneous chronic airway disease with a steadily rising global prevalence. Emerging evidence positions epithelial barrier integrity as a central determinant of asthma development and progression. The airway epithelium executes coordinated physical, immune-surveillance, and anti-oxidative functions; disruption of tight junctions, adherens junctions, or desmosomes initiates chronic inflammation, microbiome dysbiosis, and airway remodeling. Genome-wide studies have identified barrier-enriched susceptibility genes—such as protocadherin-1, cadherin-related family member 3, while epigenome-wide analyses highlight DNA methylation, histone modifications, and microRNA dysregulation as pivotal regulators of disease risk. Clinically, both Type 2-high and Type 2-low phenotypes share epithelial barrier dysfunction yet differ markedly in inflammatory cell profiles, pharmacologic responsiveness, and remodeling patterns. Biologic agents targeting TSLP, IL-33, IL-4/IL-13, and IL-5 have reshaped the management of severe asthma by attenuating exacerbations and mitigating structural damage; concurrently, histone deacetylase modulators and microRNA-based approaches are emerging as innovative epigenetic interventions. Integration of genetic and epigenetic signatures with robust barrier assessments is anticipated to refine phenotypic stratification and enable truly personalized therapies, driving the next phase of precision medicine in asthma.