溶酶体-线粒体轴心机制在重度烧伤全身血管内皮细胞损伤发生中的作用

The enhancement of blood vessel permeability in severe thermal injury, leads to the loss of plasma, severe shock amd death.Endothelial cells along with the blood vessel are the most important barrier to keep the blood volumn. Research work on the regulation of blood vessel permeability mostly focuses on the para-cellular and intra-celluar mechanism of endothelium, while our recent study by ultra-structure microscopy found that it was not only para- and intran-cellular mechanism on regulation of endothelium permeability when burned, severe endothelial cells damage occoured even in the distant blood vessels (such as arota) to the local injury area (such as burned at the back of the animal). Our previous studies show that oxidative-stress-induced program cell death might be mitochodira-independent, namely lysosomal-mitochondrial axis theroy of apoptosis. Moderate lysosomal damage is an early event compared to the mitochondrial damage, and the apoptosis can be prevented by iron chelator, which protects both lysosomes and mitochondrion. This study try to explore the mechanism of severe thermal injury-induced endothelial damage, and the role of lysosomal-mitochondrial axis theroy in it. To find a new therapy against this severe trauma, we will testify whether iron chelator-deferiprone will have protective effect against thermal injury at animal model level.

大面积重度烧伤引起血管通透性增高，大量血浆丢失导致低血容量性休克，是临床上烧伤病人死亡的重要原因。血管内皮细胞屏障功能是血容量保持的重要器官。大量的基础研究集中在内皮细胞旁路和内路通透性调节机制，然而我们利用电子显微镜观察发现，局部的烧伤（例如背部）不仅引起细胞内皮旁路和内路通透性调节机制的改变，甚至导致远端（例如主动脉）细胞的严重损伤。我们前期的研究发现，应激反应导致的细胞凋亡存在着一个非线粒体依赖性机制，即溶酶体-线粒体轴心学说。溶酶体的损伤是细胞凋亡的早期表现，应用铁离子鏊合剂阻断氧应激反应，可以达到保护溶酶体，继而保护线粒体的作用。本项目旨在探讨大面积重度烧伤引起的血管内皮细胞损伤机制，及溶酶体-线粒体轴心学说在其中的作用，以及在动物水平验证铁离子鏊合剂在重度烧伤的保护作用，为临床救治大面积烧伤病人提供新的思路和办法。

局部烧伤会引起全身血管通透性增高、循环系统紊乱，经常导致多器官的衰竭。导致这些致命状况的通常解释是炎症细胞因子以及活性氧直接诱导内皮细胞收缩损伤，从而提高血管的通透性。我们最近在大鼠背部烧伤后即刻血管灌注固定液，并行电镜观察发现远端的大血管例如主动脉内皮细胞呈现严重的超微结构的损伤。体外实验证实，烧伤血清引起溶酶体、线粒体和细胞的凋亡坏死。应用水溶性的铁离子螯合剂（去铁酮）可以大大地阻止这个现象的发生，而应用溶酶体蛋白酶抑制剂（pepstatin A）可以阻止烧伤血清诱导的线粒体损伤和细胞凋亡。进一步研究发现，烧伤后应用去铁酮腹腔注射可以大大地提高烧伤动物的存活率，提高尿量、血浆SOD，降低血浆MDA。这些结果提示，早期给予烧伤动物低分子水溶性的铁离子螯合剂，可以大大降低铁离子介导的溶酶体氧化应激，保护内皮细胞的溶酶体以及其后线粒体损伤，从而为临床上救治重度烧伤系统性器官衰竭提供新思路。