Role of Vasodilator Stimulated Phosphoprotein (VASP) during Hypoxia, Inflammation and Ischemia-Reperfusion Injury.

有限的氧气供应(缺氧)是各种病理条件的最终结果，如休克、败血症和炎症。缺氧和急性炎症过程导致细胞骨架的构象变化。这一过程与细胞屏障的破坏有关，细胞屏障是人类有机体捍卫其完整性的支柱，可能导致器官功能障碍。血管扩张剂磷酸刺激蛋白(Vasp)是一种重要的胞浆肌动蛋白结合蛋白，控制细胞旁通透性和血小板的激活。VASP在低氧状态下表达降低，导致细胞内皮细胞和上皮屏障功能降低。这对全身炎症和缺血再灌注损伤期间的器官保护具有重要意义。我们的初步数据表明，VASP在急性肺损伤和低氧期间对肺泡-毛细血管屏障起关键作用。VASP在心肌、肝脏和胃肠道缺血再灌注损伤过程中也有显著影响，对胃肠屏障特性也有显著影响。因此，我们建议在急性炎症、缺氧和缺血再灌注损伤过程中探讨VASP和VASP的表达在血管完整性和器官功能中的作用。综上所述，这些研究旨在确定在缺氧、急性炎症和再灌注损伤条件下维持器官功能和完整性的新的先天代谢和转录途径。这些发现的延伸将有助于在危重疾病的治疗中确定新的分子靶点。

Limited oxygen availability (hypoxia) is the end result for a variety of pathological conditions, such as shock, sepsis and inflammation. Hypoxia and acute inflammatory processes results in conformational changes of the cytoskeleton. This process is associated with a disruption of cellular barriers, a mainstay of the human organism to defend its integrity and might result in organ dysfunction. Vasodilator phosphostimulated protein (VASP) is a crucial cytoplasmatic actin binding protein controlling paracellular permeability as well as activation of thrombocytes. VASP expression is reduced during periods of hypoxia resulting in reduced cellular endothelial and epithelial barrier function. This has significant implications on organ protection during periods of systemic inflammation and ischemia reperfusion-injury. Our preliminary data demonstrate a crucial role of VASP for the alveolar-capillary barrier during acute lung injury and during periods of hypoxia. VASP also has significant impact during myocardial, hepatic and gastrointestinal ischemiareperfusion injury and on gastrointestinal barrier properties. Therefore we propose here to investigate the role of VASP and VASP expression on the vascular integrity and organ function during periods of acute inflammation, hypoxia and ischemiareperfusion injury. Taken together, these studies are aimed to identify novel innate metabolic and transcriptional pathways to maintain organ function and integrity during conditions of hypoxia, acute inflammation and reperfusion-injury. Extensions of these findings will help to identify novel molecular targets in the treatment of critical illnesses.