Microvascular Barrier Dysfunction in Thermal Trauma

热损伤是一种常见的创伤形式，具有显著的死亡率和发病率。尽管重症监护和伤口管理有了显著的改善，但以多器官水肿和功能障碍为特征的全身炎症反应的终末器官影响仍然是严重烧伤患者危及生命的问题。人们非常关注微血管屏障功能障碍的发展，这是炎症性水肿的基本细胞过程，但尚未在分子水平上理解。本项目的总体目标是确定微血管对热创伤的高渗透性反应的关键信号分子和结构成分。在此背景下，提出了一个主要假设，即Src酪氨酸激酶信号传导内皮细胞骨架收缩和连接紊乱诱导热损伤期间微血管屏障功能障碍。相应的，将实现四个具体目标：1)表征烧伤引起的微血管渗漏；2)研究内皮细胞骨架收缩导致微血管高通透性的机制；3)阐明ve -钙粘蛋白连接紊乱在介导内皮屏障功能障碍中的作用；4)验证Src在调节细胞骨架和连接结构和功能中的共同信号作用。本研究将结合药理学方法和分子生物学技术，使用临床相关的烫伤大鼠模型来验证这些假设。该研究将为内皮屏障功能的细胞和分子控制提供新的见解。从这项研究中获得的信息将增强我们对微血管病理生物学的认识，不仅是烧伤，还有其他类型的与炎症反应相关的损伤。此外，识别直接导致微血管高通透性的信号或结构分子将导致针对损伤过程的新治疗靶点的开发。

Thermal injury represents a common form of trauma associated with significant mortality and morbidity. Despite the remarkable improvements in critical care and wound management, end-organ effects of systemic inflammatory reactions characteristic of multiple organ edema and dysfunction remain life-threatening problems in patients with major burns. Of great concern is the development of microvascular barrier dysfunction, a fundamental cellular process underlying inflammatory edema that has yet to be understood at the molecular level. The overall goal of this project is to identify key signaling molecules and structural components responsible for the microvascular hyperpermeability response to thermal trauma. Within this context, a major hypothesis is developed stating that Src tyrosine kinase-signaled endothelial cytoskeletal contraction and junctional disorganization induce microvascular barrier dysfunction during thermal injury. Correspondingly, four specific aims will be achieved: 1) to characterize burn-induced microvascular leakage; 2) to examine the mechanism by which endothelial cytoskeletal contraction causes microvascular hyperpermeability; 3) to elucidate the role of VE-cadherin junctional disorganization in mediating endothelial barrier dysfunction; and 4) to verify the common signaling role of Src in the regulation of cytoskeletal and junctional structure and function. The study will test the hypotheses using a clinically relevant rat model of scald burn in combination with pharmacological approaches and molecular biology techniques. The study will provide new insights into the cellular and molecular control of endothelial barrier function. Information derived from this study will enhance our knowledge on microvascular pathobiology of not only burns but also other types of injuries associated with inflammatory responses. Furthermore, identification of signaling or structural molecules directly responsible for microvascular hyperpermeability should lead to the development of new therapeutic targets specific to the injurious process.