Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome (ARDS), which carries a high mortality. Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. Objective: To determine whether endogenous circulating BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during LPS-induced lung inflammation and permeability. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Inhaled LPS was used as a murine model of acute lung injury to evaluate the impact of BMP9 in vivo. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Potential mechanisms were delineated by transcript analysis in human primary lung endothelial cells. Main Results: Subacute neutralization of endogenous circulating BMP9 in mice resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In mice exposed to LPS, BMP9 levels were markedly reduced, due to a temporary reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. Augmentation of BMP9 signalling with exogenous BMP9 in LPS-challenged mice prevented lung injury and edema. In human sepsis patients, circulating levels of BMP9 were also markedly reduced. In lung endothelial cells, BMP9 regulated a programme of gene expression controlling vascular permeability including AQP1 (encoding aquaporin-1), KDR (encoding VEGFR2), TEK (encoding Tie2), and pathways involved in cell membrane integrity. Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Supplementation with exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in the setting of lung injury.

中文翻译：

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循环中的BMP9在小鼠炎症性肺损伤中保护肺内皮

理由：肺血管内皮通透性导致高通透性肺水肿，这是急性呼吸窘迫综合征（ARDS）的特征，急性呼吸窘迫综合征具有很高的死亡率。循环骨形态发生蛋白9（BMP9）新兴成为肺血管稳态的重要调节剂。目的：确定内源性循环中的BMP9是否在维持肺血管内皮完整性中起作用，以及在LPS诱导的肺部炎症和通透性过程中是否发生内源性BMP9的丢失。方法：向成年健康小鼠施用BMP9中和抗体，并检查其肺血管。吸入的LPS被用作急性肺损伤的小鼠模型，以评估BMP9在体内的影响。测量败血症和内毒素血症小鼠的血浆中BMP9的水平。通过人类原发性肺内皮细胞中的转录本分析描述了潜在的机制。主要结果：小鼠内源性循环BMP9的亚急性中和导致肺血管通透性增加，间质水肿和中性粒细胞外渗。在暴露于LPS的小鼠中，由于肝BMP9 mRNA表达的暂时减少和血浆中弹性蛋白酶活性的增加，BMP9水平显着降低。在LPS攻击的小鼠中，外源BMP9增强BMP9信号传导可预防肺损伤和水肿。在人类败血症患者中，BMP9的循环水平也明显降低。在肺内皮细胞中，BMP9调节了控制血管通透性的基因表达程序，包括AQP1（编码aquaporin-1），KDR（编码VEGFR2），TEK（编码Tie2），和涉及细胞膜完整性的途径。结论：内源性循环BMP9是一种肺内皮保护因子，在炎症过程中被下调。补充外源性BMP9提供了一种潜在的疗法，可以防止在肺损伤的情况下增加肺血管内皮通透性。