脊髓损伤大鼠交感活性对基质金属蛋白酶及其内源性组织抑制因子影响的机制研究

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMP) play an important role in cardiovascular remodelling. According to the published literatures and our previous research, MMPs and TIMP were upregulated in animals with spinal cord injury (SCI). It is implied that expression and activity of MMP/TIMP is related to the vascluar structure and control of blood pressure (BP) after SCI. In this study, a rat model of T3-spinal cord contusion is established. Expression of MMP-2, MMP-9, TIMP1 as well as activity of JNK, ERK, NF-κB signaling pathways in the spinal cord and the mesenteric artery are observed. Fibroblasts are extracted from mesenteric artery and cultured in vitro. Expression and activity of MMP-2, MMP-9, TIMP1 stimulated by exogenous norepinephrine are tested in several conditions that different signaling pathway are blocked. Hence, regulation of MMP and TIMP by sympathetic activity is investigated on histological, cellular and molecular levels, which may help the better understanding of the underlying mechanisms regarding changes in vascluar structure and control of BP after SCI.

基质金属蛋白酶（matrix metalloproteinases，MMPs）及其组织抑制因子（tissue inhibitors of metalloproteinase，TIMP）在心脏及血管重构过程中具有重要作用。已有文献和我们的前期研究发现脊髓损伤大鼠MMP/TIMP表达均上调，故推测脊髓损伤后MMP/TIMP表达及活性变化可能与血管结构改变j及血压调控异常的发生有关。本研究拟建立大鼠T3脊髓损伤模型，观察脊髓组织及肠系膜动脉MMP-2、MMP-9、TIMP1表达及相关调控通路JNK、ERK、NF-κB的活性变化；利用体外培养的大鼠肠系膜动脉成纤维细胞，在控制上述调控通路活性的条件下观察MMP-2、MMP-9、TIMP1表达及活性变化，明确交感神经递质对MMP-2、MMP-9、TIMP1的调控方式。从而在组织、细胞及分子等多个水平探索脊髓损伤后交感活性异常所致的血管结构改变及其机制。

基质金属蛋白酶（matrix metalloproteinases，MMPs）及其组织抑制因子（tissue inhibitors of metalloproteinase，TIMP）在心脏及血管重构过程中具有重要作用。已.有文献和我们的前期研究发现脊髓损伤大鼠MMP/TIMP表达均上调，故推测脊髓损伤后MMP/TIMP表达及活性变化可能与血管结构改变j及血压调控异常的发生有关。本项目建立大鼠T3脊髓横断及挫伤模型，并通过直肠扩张法反复诱发自主神经反射异常引起交感神经系统的过度兴奋，检测损伤后大鼠脊髓、血管壁中MMP-2、MMP-2及TIMP1的mRNA转录及蛋白表达水平，初步验证脊髓损伤对MMP-2、MMP-9及TIMP1表达及活性的影响；检测脊髓及血管壁组织中JNK、ERK、NF-κB途径中关键信号蛋白c-Jun、ERK1/2、IκB水平，观察脊髓损伤后血管系统上述通路活性的变化。现有初步实验数据表明，脊髓损伤后脊髓及血管系统MMP-2、MMP-9及TIMP1表达上调；脊髓损伤后脊髓及血管系统JNK、ERK、NF-κB通路有不同程度的激活；交感活性改变通过JNK、ERK、NF-κB通路对MMP/TIMP表达进行调控，从而参与了脊髓损伤后自主神经反射异常的发生。