Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.
Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.
复制标题
循环BMP 9在小鼠炎症诱导的肺损伤期间保护肺内皮细胞。
DOI：
10.1164/rccm.202005-1761oc
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发表时间：
2021-06-01
影响因子：
24.7
通讯作者：
Morrell NW
中科院分区：
文献类型：
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作者：
Li W;Long L;Yang X;Tong Z;Southwood M;King R;Caruso P;Upton PD;Yang P;Bocobo GA;Nikolic I;Higuera A;Salmon RM;Jiang H;Lodge KM;Hoenderdos K;Baron RM;Yu PB;Condliffe AM;Summers C;Nourshargh S;Chilvers ER;Morrell NW
基本原理：肺内皮细胞的通透性导致了以急性呼吸窘迫综合征为特征的高通透性肺水肿。循环BMP 9（骨形态发生蛋白9）正在成为肺血管稳态的重要调节因子。目的：确定内源性BMP 9是否在保护肺内皮完整性中起作用，以及在LPS攻击期间是否发生内源性BMP 9的损失。方法：将BMP 9中和抗体注射到健康成年小鼠，观察肺血管。通过人肺内皮细胞中的转录本分析描绘了潜在的机制。在由吸入LPS诱导的鼠急性肺损伤模型中评估BMP 9施用的影响。在来自脓毒症患者和来自内毒素血症小鼠的血浆中测量BMP 9的水平。测量和主要结果：与IgG对照治疗（N = 6）相比，小鼠（N = 12）中内源性BMP 9的亚急性中和导致肺血管通透性增加（P = 0.022）、间质水肿（P = 0.0047）和中性粒细胞外渗（P = 0.029）。在肺内皮细胞中，BMP 9调节与血管通透性和细胞膜完整性有关的转录组通路。小鼠（N = 8）中BMP9信号传导的增强防止吸入LPS诱导的肺损伤（P = 0.0027）和水肿（P < 0.0001）。在内毒素血症小鼠（N = 12）中，内源性循环BMP 9浓度显著降低，其原因包括肝脏BMP 9 mRNA表达的短暂降低和血浆中弹性蛋白酶活性的增加。在患有脓毒症的人类患者（N = 10）中，BMP9的循环浓度也显著降低（P < 0.0001）。结论：内源性循环BMP 9是一种肺内皮保护因子，在炎症过程中下调。外源性BMP 9提供了一种潜在的治疗方法，以防止肺损伤中肺内皮通透性增加。
Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS–induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.