内皮损伤为脓毒症发生发展的重要环节。我们研究证实，脓毒症时AngⅡ升高导致内皮损伤。肝素结合生长因子（Midkine，MK）增加ACE生成，促进AngⅠ向AngⅡ转换，但其对内皮的影响尚不清楚。预实验见脓毒症时MK升高，我们推测脓毒症时MK通过ACE-AngⅡ途径介导内皮损伤。而MK调控ACE的机制与膜受体Notch2有关。本研究拟通过①细胞实验用内毒素刺激内皮细胞和Notch2敲除的内皮细胞，观察MK、ACE、AngⅡ水平及内皮功能，明确MK/Notch2在内皮损伤中的作用。②细胞实验用MK刺激内皮细胞，分别阻断Notch2、ACE、AngⅡ，明确MK/Notch2通过ACE-AngⅡ介导内皮损伤的机制。③利用脓毒症小鼠模型，分别阻断MK和AngⅡ，验证MK通过AngⅡ介导内皮损伤。④临床研究明确脓毒症时MK水平与内皮损伤的关系，为脓毒症内皮损伤的防治开辟新的调控途径。

Endothelial injury plays an important role in sepsis. Our research found AngⅡinduced endothelial injury in sepsis. Midkine is a novel regulator of AngⅡsignaling, which might play an important role in septic endothelial injury. The preliminary experiment showed midkine increased in sepsis. Our hypothesis is midkine inducing endothelial injury by the ACE-AngⅡpathway, which need Notch2 participating. In this study, the role and molecular mechanism of midkine in septic endothelial injury will be investigated by vitro study. Then the LPS- induced sepsis model will be used to verify the role and mechanism of midkine in septic endothelial injury in vivo. Meanwhile, the relationship between midkine level and severity of sepsis and endothelial injury will be investigated by clinical trial. All above is to provide evidence for the role and mechanism of midkine induced endothelial injury in sepsis.