Roles of c-kit in development and pathophysiology of smooth muscle

c-kit 在平滑肌发育和病理生理学中的作用

基本信息

批准号：
13670091
负责人：
TOKUTOMI Yoshiko
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Drug-induced contraction of gastrointestinal tracts seems to depend upon the extent of their rhythmic contraction that is driven by the activity of gastrointestinal pacemaker cells. In BALB/c mice chronically administered with a neutralizing anti-c-Kit monoclonal antibody (ACK2), rhythmic contraction of gastrointestinal tract was impaired and contractile responses to drugs., including acetylcholine, prostaglandin F_<2α> and bradykinin were anomalously augmented. Histochemical analysis of the c-kit positive cells in the gastrointestinal tract revealed the decreased number of c-kit positive cells in the ACK2-treated animals, which lead to the impaired rhythmic contraction. Since the intestinal c-kit positive cells in primary culture developed Ca^<2+>-dependent rhythmic Cl^-current, the rhythmic current is supposed to be an origin of gastrointestinal pacemakers. The extent of anomaly in drug-induced contraction correlated with the extent of impairment in rhythmic contraction. The anomalou … More s drug-induced contraction in the preparation from ACK2-treated animals, which is accompanied by the impaired rhythmic contraction, was mimicked when the gastrointestinal segments from control animals were superfused with a low temperature organ bath solution at 25℃. These results suggest that rhythmic discharge of excitation of smooth muscle cells, which is triggered by rhythmic excitatory input from c-kit cells, regulates the extent of drug-induced contraction.We have demonstrated that human α_1-acid glycoprotein produces a transient relaxation in the mouse aorta precontracted with phenylephrine. It is more likely that the α_1-acid glycoprotein-induced relaxation is due to block of Ca^<2+>-entry through VDCC or NSCC in the smooth muscle cells rather than activation of endothelial NO pathway. The transient relaxation induced by α_1-acid glycoprotein might occur as prolonged relaxation in the peripheral blood vessel, which may result in improvement of the blood circulation at tissue with inflammation. Less

胃肠道的药物诱导的收缩似乎取决于其节奏收缩的程度，而胃肠道的起搏器细胞的活性则驱动。在BALB/C小鼠中，长期用中和抗C-KIT单克隆抗体（ACK2）施用，胃肠道的节奏收缩受损，对药物的收缩反应受损。胃肠道中C-KIT阳性细胞的组织化学分析表明，ACK2处理的动物中C-KIT阳性细胞数量减少，从而导致节奏收缩受损。由于原代培养物中的肠道C-kit阳性细胞产生了Ca^<2+> - 依赖性的节奏Cl^corrent，因此预计有节奏的电流是胃肠道起搏器的起源。药物诱导的收缩的异常程度与节奏收缩障碍的程度相关。 ANOMALOU…在ACK2处理的动物制备中，更多的药物诱导的收缩是通过节奏收缩受损而完成的，当对照动物的胃肠道片段用低温器官浴溶液超过25°时，可以模仿受损的节奏收缩。这些结果表明，平滑肌细胞兴奋的节奏消除，这是由C-KIT细胞的节奏兴奋输入引起的，它调节了药物诱导的收缩程度。我们已经证明了人α_1-酸糖蛋白在小鼠主动脉（与骨素）中产生短暂的糖蛋白会产生短暂的放松。 α_1酸糖蛋白诱导的松弛更有可能是由于Ca^<2+> - 通过VDCC或NSCC进入平滑肌细胞中的块，而不是激活内皮NO途径。 α_1酸糖蛋白引起的瞬时弛豫可能会随着外周血血管的延长弛豫而发生，这可能会导致注射液在组织中血液循环的改善。较少的