Program for Lung and Vascular Biology and Section for Injury Repair and Regeneration Research, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sci Transl Med. 2023 Aug 16;15(709):eabm5755. doi: 10.1126/scitranslmed.abm5755.
Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury and high mortality in aged mice after sepsis challenge were attributable to impaired endothelial regeneration and vascular repair. Genetic lineage tracing study showed that endothelial regeneration after sepsis-induced vascular injury was mediated by lung resident endothelial proliferation in young adult mice, whereas this intrinsic regenerative program was impaired in aged mice. Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic expression or in vivo endothelium-targeted nanoparticle delivery of the gene driven by an endothelial cell (EC)-specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. Mechanistically, aging-induced promoter hypermethylation in mice, which could be inhibited by decitabine treatment, inhibited induction after sepsis challenge. In COVID-19 lung autopsy samples, was not induced in vascular ECs of elderly patients in their 80s, in contrast with middle-aged patients (aged 50 to 60 years). Thus, reactivation of FoxM1-mediated endothelial regeneration and vascular repair may represent a potential therapy for elderly patients with ARDS.
衰老（aging）是急性呼吸窘迫综合征（ARDS）高发病率和高死亡率的一个主要危险因素。在这里，我们证明了脓毒症（sepsis）后老年小鼠肺部持续损伤和高死亡率归因于内皮再生（endothelial regeneration）受损和血管修复（vascular repair）障碍。遗传谱系追踪研究（genetic lineage tracing study）显示，年轻成年小鼠在脓毒症诱导的血管损伤后，内皮再生是由肺驻留内皮细胞（lung resident endothelial cells）增殖介导的，而这种内在的再生程序在老年小鼠中受损。在老年小鼠的肺部，叉头框 M1（forkhead box M1，FoxM1）的表达，一种年轻小鼠内皮再生的重要介质，并没有被诱导。FoxM1 基因的表达或体内内皮靶向纳米颗粒（endothelium-targeted nanoparticle）传递，由内皮细胞（endothelial cell，EC）特异性启动子驱动，可重新激活内皮再生，使血管修复和炎症消退正常化，并促进脓毒症后老年小鼠的存活。此外，用 FDA 批准的去甲基化药物地西他滨（decitabine）治疗足以重新激活老年小鼠依赖 FoxM1 的内皮再生，逆转衰老导致的炎症损伤消退障碍，并促进存活。从机制上讲，衰老诱导的小鼠 基因启动子超甲基化（hypermethylation）可被地西他滨治疗抑制，抑制了脓毒症后的诱导。在 COVID-19 肺尸检样本中，血管内皮细胞（vascular endothelial cells）中未诱导出 ，而在 80 多岁的老年患者中，与中年患者（年龄在 50 至 60 岁之间）形成对比。因此，重新激活 FoxM1 介导的内皮再生和血管修复可能代表 ARDS 老年患者的一种潜在治疗方法。
