我们前期报道p38 MAPK参与烧伤引起血管内皮细胞应力纤维形成，造成细胞间紧密联结损伤引起血管通透性增高。同时电子显微镜观察发现，皮肤烧伤能够引起深层主动脉内皮细胞凋亡坏死。国内第三军医大学也报道，重症烧伤病人主要脏器血管内皮细胞均有不同程度损伤和脱落，血液循环中游离内皮细胞明显增加。本课题研究烧伤后血管内皮细胞损伤发生机理。预实验表明，应用失活型p38腺病毒干预，可以大大改善烧伤动物血管损伤；采用酵母双杂交技术发现p38与HPC2蛋白结合，p38激活HPC2可抑制CDC2表达、诱导内皮细胞G2/M期阻滞，导致细胞凋亡。因此我们提出p38-CDC2信号途径参与烧伤血管内皮损伤假说。本项目拟进一步探讨HPC2磷酸化位点、抑制性转录因子复合物包括HPC2与Ring1、Bmi、Rb结合，调控E2F转录因子以及CDC2表达和细胞凋亡；观察阻断这一信号途径防治重症烧伤远端脏器损伤的可能性。

We previously reported that p38 MAPK involved in thermal injury induced vascular permeability enhancement, stress fiber formation and ensuing damage of para-cellular tight junction in endothelial cells. When we try to confirm this findings in vivo using electronic microscopy, we found that some of aorta endothelial cells had severe apoptosis. Similar observations were also reported by The Third Military Medical University, that there were endothelial cells damage in major organs and more free endothelial cells in blood circulation in severe burned patients. Our preliminary studies indicated animal vascular damage was very much improved by using adeno-viral approach of dominant negative p38 MAPK to interfere on burns animal model. Using yeast two-hybrid system technique, we found p38 MAPK bound to HPC2 protein. Activation of HPC2 by p38 MAPK inhibited CDC2 protein expression, induced endothelial cells G2/M arrest and ensuing apoptosis. So that we raise a hypothesis that p38 – CDC2 signal pathway involves thermal injury-induced blood vessel endothelial cells damage. In this study, we will further investigate HPC2 phosphorylation site by p38 MAPK, and molecular mechanism on inhibition of CDC2 promoter, including the inhibitory complex formation, such as HPC2 binds to Ring1, Bmi, Rb proteins, and their role on regulation of E2F transcription factor mediated CDC2 expression. Furthermore, we will investigate how the apoptosis induced when CDC2 expression inhibited. Using molecular biology method to interfere this pathways, we will try to develop a new therapeutic method against thermal injury-induced endothelial cell damage, and find new target molecules against sever thermal injury, remote organs and even multiple organs damage.