Gallagher Diana C, Parikh Samir M, Balonov Konstantin, Miller Andrew, Gautam Shiva, Talmor Daniel, Sukhatme Vikas P
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Shock. 2008 Jun;29(6):656-61. doi: 10.1097/shk.0b013e31815dd92f.
There are few blood biomarkers predictive of mortality in adult respiratory distress syndrome (ARDS), and none that currently serve as therapeutic targets. Here, we ask whether a circulating protein angiopoietin 2 (Ang2) correlates with severity of lung injury and mortality in a surgical intensive care unit cohort with acute lung injury (ALI)/ARDS. Tie 2 is a tyrosine kinase receptor expressed on endothelial cells. One ligand, angiopoietin 1, phosphorylates Tie 2 and stabilizes adult vasculature. An alternate ligand, Ang2, serves as a context-dependent antagonist and disrupts barrier function. Previously, our laboratory detected high circulating Ang2 levels in septic patients and a correlation with low Pa(O2)/F(IO2). In this study, daily plasma was collected in 63 surgical intensive care unit patients. Eighteen patients met clinical criteria for ALI or ARDS. The median Ang2 at admission in patients who never developed ALI/ARDS was 3.7 ng/mL (interquartile range [IQR], 5.6; n = 45). The Ang2 on the day a patient met criteria for ALI/ARDS was 5.3 ng/mL (IQR, 6.7) for survivors (n = 11) and 19.8 ng/mL (IQR, 19.2) for nonsurvivors (n = 7; P= 0.004). To explore the mechanism of high Ang 2 leading to increased permeability, plasma from patients with ALI was applied to cultured lung endothelial cells and found to disrupt normal junctional architecture. This effect can be rescued with the Tie 2 agonist angiopoietin 1. A patient's convalescent (low Ang2) plasma did not disrupt junctional architecture. Although further studies with larger sample sizes will be needed to confirm these results, high Ang2 in critically ill patients with ALI/ARDS is associated with a poor outcome. These data, coupled with our cell culture experiments, suggest that antagonism of Ang2 may provide a future novel therapeutic target for ARDS.
几乎没有血液生物标志物可预测成人呼吸窘迫综合征（ARDS）的死亡率，目前也没有可作为治疗靶点的标志物。在此，我们探讨在一个急性肺损伤（ALI）/ARDS外科重症监护病房队列中，循环蛋白血管生成素2（Ang2）是否与肺损伤严重程度及死亡率相关。Tie 2是一种在内皮细胞上表达的酪氨酸激酶受体。一种配体血管生成素1可使Tie 2磷酸化并稳定成人血管系统。另一种配体Ang2则作为一种依赖于环境的拮抗剂，破坏屏障功能。此前，我们实验室在脓毒症患者中检测到循环Ang2水平升高，并发现其与低动脉血氧分压/吸入氧分数值（Pa[O₂]/F[IO₂]）相关。在本研究中，我们收集了63例外科重症监护病房患者的每日血浆样本。18例患者符合ALI或ARDS的临床标准。从未发生ALI/ARDS的患者入院时Ang2的中位数为3.7 ng/mL（四分位间距[IQR]，5.6；n = 45）。符合ALI/ARDS标准当天，幸存者（n = 11）的Ang2为5.3 ng/mL（IQR，6.7），非幸存者（n = 7）为19.8 ng/mL（IQR，19.2）；P = 0.004。为探究高Ang2导致通透性增加的机制，我们将ALI患者的血浆应用于培养的肺内皮细胞，发现其破坏了正常的连接结构。Tie 2激动剂血管生成素1可挽救这种效应。患者恢复期（低Ang2）血浆未破坏连接结构。尽管需要更大样本量的进一步研究来证实这些结果，但ALI/ARDS重症患者中高Ang2与不良预后相关。这些数据，结合我们的细胞培养实验，提示拮抗Ang2可能为ARDS提供一个未来新的治疗靶点。
