Following hemorrhagic shock (HS), vascular hyperpermeability i.e. the leakage of fluid, nutrients and proteins into the extravascular space occurs primarily due to the disruption of the endothelial cell-cell adherens junctional complex. Studies from our laboratory demonstrate that activation of the mitochondria mediated 'intrinsic' apoptotic signaling cascade has a significant role in modulating HS-induced hyperpermeability. Here we report the novel use of recombinant Bcl-xL, an anti-apoptotic protein, to control HS-induced vascular hyperpermeability. Our results corroborate involvement of vascular hyperpermeability and apoptotic signaling. Hemorrhagic shock (HS) (mean arterial pressure [MAP] was reduced to 40 mmHg for 60 minutes followed by resuscitation to 90 mmHg for 60 minutes) in rats resulted in vascular hyperpermeability as determined by intra-vital microscopy. Treatment of Bcl-xL (2.5ug/ml of rat blood in non-lipid cationic polymer, i.v.) before, during and even after HS attenuated or reversed HS-induced vascular hyperpermeability significantly (p<0.05). Conversely, treatment using Bcl-xL inhibitors, 2-methoxy antimycin (2-MeOAA) and ABT 737, significantly increased vascular hyperpermeability compared to sham (p<0.05). Bcl-xL treatment also decreased the amount of fluid volume required to maintain a MAP of 90 mmHg during resuscitation (p<0.05). HS resulted in increased mitochondrial ROS formation, reduction of ΔΨm, mitochondrial release of cytochrome c and significant activation of caspase-3 (p<0.05). All of these effects were significantly inhibited by Bcl-xL pre-treatment (p<0.05). Our results show that recombinant Bcl-xL is effective against HS-induced vascular hyperpermeability that appears to be mediated through preservation of ΔΨm and subsequent prevention of caspase-3 activation.

中文翻译：

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重组BCL-XL在失血性休克大鼠模型中减弱了血管的通透性。

失血性休克（HS）后，血管通透性过高，即液体，营养物和蛋白质向血管外空间的渗漏主要是由于内皮细胞-细胞粘附连接复合物的破坏。我们实验室的研究表明，线粒体介导的“固有”凋亡信号级联反应的激活在调节HS诱导的通透性方面具有重要作用。在这里，我们报告了重组Bcl-xL，一种抗凋亡蛋白，用于控制HS诱导的血管通透性过高的新型用途。我们的结果证实了血管通透性和凋亡信号的参与。大鼠的失血性休克（HS）（平均动脉压[MAP]降低至40 mmHg，持续60分钟，然后复苏至90 mmHg，持续60分钟），通过活体显微镜确定，导致血管通透性过高。在HS之前，期间以及之后，Bcl-xL（非脂质阳离子聚合物中的大鼠血液中2.5ug / ml静脉注射）的治疗显着减弱或逆转了HS诱导的血管通透性（p <0.05）。相反，与假手术相比，使用Bcl-xL抑制剂，2-甲氧基抗霉素（2-MeOAA）和ABT 737的治疗显着提高了血管的通透性（p <0.05）。Bcl-xL治疗还减少了复苏期间维持MAP达到90 mmHg所需的体液量（p <0.05）。HS导致线粒体ROS形成增加，ΔΨm降低，细胞色素c的线粒体释放和caspase-3的显着激活（p <0.05）。Bcl-xL预处理可显着抑制所有这些作用（p <0.05）。我们的结果表明，重组Bcl-xL可有效抵抗HS诱导的血管通透性过高，后者似乎是通过保留ΔΨm和随后阻止caspase-3激活来介导的。