SDF-1/CXCR4生物轴参与H2S救治创伤失血性休克机制的研究

As the intermediate links during shock development, the inflammatory response plays a role of "amplifier". So inhibiting the inflammatory response during shock is helpful for preservation and recovery of organs function. Our previous research indicated that exogenous H2S could obviously inhibit the early inflammatory response to different animal models of traumatic shock, and improve the survival rate of those traumatic shock animals. Stromal cell derived factor-1 (SDF-1) and CXCR4 (SDF-1 receptor) could regulate the recruitment, migration and transmembrane transfer of many kinds of inflammatory cells, and promote the inflammatory cells to secrete various cytokines involved in the early inflammatory response. We hypothesize that exogenous H2S may inhibit the migration of inflammatory cells through regulation of SDF-1/CXCR4 biological axis, prevent the release of inflammatory cytokines during the early period of shock, and stop the cascade amplification process of the inflammatory response. We are intended to study the regulation of exogenous H2S on SDF-1/CXCR4 biological axis, and explore the mechanism of H2S on treatment of traumatic hemorrhagic shock, using the animal model of traumatic hemorrhagic shock.

炎症反应作为休克发展过程中的中间环节，起到了"放大器"的作用。因此，抑制休克过程中炎症反应，有利于组织器官功能的保存和后期复苏。我们前期的研究发现，外源性H2S可明显抑制不同创伤休克动物模型的早期炎症反应，提高创伤休克动物的生存率。基质衍生因子（Stromal cell derived factor-1, SDF-1）及其受体CXCR4可以调控包括炎症细胞在内的多种类型细胞的募集、游走与跨膜转移，并促进细胞分泌各种细胞因子参与了早期炎症反应。我们设想外源性H2S可通过调节SDF-1/CXCR4生物轴抑制炎症细胞的迁徙，切断了休克早期的炎症因子释放，阻止了炎症反应的级联放大过程。本项目拟利用大鼠创伤失血性休克模型，通过H2S对SDF-1&CXCR4轴路功能调节的研究，探讨外源性H2S用于创伤失血性休克救治的机制。

炎症反应作为休克发展过程中的中间环节，起到了“放大器”的作用。因此，抑制休克过程中炎症反应，有利于组织器官功能的保存和后期复苏。我们前期的研究发现，外源性H2S可明显抑制不同创伤休克动物模型的早期炎症反应，提高创伤休克动物的生存率。基质衍生因子1及其受体CXCR4可以调控包括炎症细胞在内的多种类型细胞的募集、游走与跨膜转移，并促进细胞分泌各种细胞因子参与了早期炎症反应。本课题研究发现外源性给予NaHS治疗能够通过抑制氧化应激和Fas/FasL凋亡信号通路对创伤失血性休克诱导的炎症反应造成的肺损伤发挥保护作用，同时发现外源性给予H2S治疗能够减轻创伤出血性休克诱导的心肌损伤，其机制为抑制心肌细胞凋亡、线粒体膜通透孔开放和凋亡相关基因表达。此外，通过体外实验证实外源性H2S可通过调节SDF-1/CXCR4通路抑制炎症细胞的迁徙，切断了休克早期的炎症因子释放，阻止了炎症反应的级联放大过程。本课题研究初步阐明了外源性H2S用于创伤失血性休克救治的机制，为临床救治创伤失血性休克提供了理论依据。