Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans.
Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans.
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DOI：
10.1371/journal.pmed.0030046
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发表时间：
2006-03
期刊：
影响因子：
15.8
通讯作者：
Sukhatme VP
中科院分区：
文献类型：
--
作者：
Parikh SM;Mammoto T;Schultz A;Yuan HT;Christiani D;Karumanchi SA;Sukhatme VP
急性呼吸窘迫综合征（ARDS）是许多潜在疾病的毁灭性并发症，最明显的是败血症。尽管病理性血管渗漏与急性呼吸窘迫综合征和败血症相关肺损伤的发病机制有关，但促进血管渗漏的机制尚不完全清楚。血管生成素-2 （Angiopoietin-2）是一种已知的内皮Tie-2受体拮抗剂，最初被描述为一种天然存在的胚胎血管正常发育的干扰物，否则由Tie-2激动剂血管生成素-1 （ang1）介导。我们假设，在脓毒症相关的肺损伤中，Ang-2有助于内皮屏障的破坏，这是一种涉及成熟脉管系统的情况。我们描述了互补的人、鼠和体外研究，这些研究表明Ang-2是这一过程的中介。我们发现，在氧合受损的脓毒症患者中，循环Ang-2显著升高。然后我们发现这些患者的血清破坏了内皮结构。人类败血症血清的这种作用与测量的Ang-2相关，随着临床改善而减弱，并被Ang-1逆转。接下来，我们发现单独使用ang2可引起内皮屏障破坏。该信号通过肌球蛋白轻链磷酸化转导。最后，我们发现，在其他健康的成年小鼠中，过量的全身ang2可引起肺泄漏和充血。我们的研究结果确定了Ang-2在破坏正常肺内皮功能中的关键作用。一系列对脓毒症患者、小鼠和培养内皮细胞的研究表明，过量的Ang-2水平可引起肺渗漏和充血，并可能导致脓毒症相关的急性呼吸窘迫综合征。
Acute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature. We describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice. Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function. A series of studies in sepsis patients, mice, and cultured endothelial cells suggest that excess levels of Ang-2 can provoke pulmonary leak and congestion and might be responsible for sepsis-associated Acute Respiratory Distress Syndrome.
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影响因子：
3.2
作者：
Marchesiello, Patrick;McWilliams, James C.;Shchepetkin, Alexander
通讯作者：
Shchepetkin, Alexander
DOI：
10.1152/ajplung.2001.281.3.l582
发表时间：
2001-09-01
影响因子：
4.9
作者：
Abdulmalek, K;Ashur, F;Hussain, SNA
通讯作者：
Hussain, SNA
影响因子：
2.9
作者：
KAMISOYAMA, H;ARAKI, Y;IKEBE, M
通讯作者：
IKEBE, M
影响因子：
8.8
作者：
Levy, MM;Fink, MP;Ramsay, G
通讯作者：
Ramsay, G
影响因子：
4.8
作者：
Iivanainen, E;Nelimarkka, L;Elenius, K
通讯作者：
Elenius, K