Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-β signaling through TGF-βR2 (transforming growth factor–β receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair. Loss of endothelial Tgfbr2 prevented autocrine Vegfa (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-βR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.

中文翻译：

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TGF-βR2信号传导协调小鼠和人体组织病毒损伤后的肺血管修复

肺血管稳态的破坏是病毒性肺炎的一个核心特征，其中内皮细胞（EC）死亡和随后的血管生成反应是严重肺损伤结果的关键决定因素。更细致地了解驱动肺内皮重建的基本机制对于促进治疗性血管修复是必要的。在这里，我们证明了流感感染后肺内皮细胞中通过 TGF-βR2（转化生长因子-β 受体 2）的 TGF-β 信号传导被激活，并且内皮细胞缺陷的小鼠转化生长因子br2表现出长期损伤和血管修复减弱。内皮细胞损失转化生长因子br2阻止自分泌血管内皮生长因子（血管内皮生长因子 α）表达、内皮增殖减少以及对肺泡气体交换至关重要的有氧细胞更新受损。通过 TGF-βR2 的血管生成反应可归因于富含亮氨酸的 α-2-糖蛋白 1，这是一种抗血管生成因子，可平衡典型的血管抑制 TGF-β 信号传导。此外，我们开发了一种靶向肺内皮的脂质纳米颗粒，肺-LNP（LuLNP）。交付血管内皮生长因子mRNA（一种关键的 TGF-βR2 下游效应子）通过 LuLNP 改善了 EC 受损的再生表型转化生长因子br2流感损伤期间缺乏。这些研究明确了 TGF-βR2 在肺内皮修复中的作用，并证明了一种高效、安全的内皮靶向 LNP 的功效，该 LNP 能够为流感感染的血管修复提供治疗性 mRNA 货物。