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

药物诱导的胃肠道收缩似乎取决于由胃肠起搏细胞的活性驱动的节律性收缩的程度，在长期给予中和性抗 c-Kit 单克隆抗体 (ACK2) 的 BALB/c 小鼠中，有节律性收缩。胃肠道收缩受损，对乙酰胆碱、前列腺素 F_<2α> 和缓激肽等药物的收缩反应减弱。对胃肠道中 c-kit 阳性细胞的组织化学分析显示，接受 ACK2 处理的动物中 c-kit 阳性细胞数量减少，导致肠道 c-kit 阳性细胞节律性收缩受损。原代培养物产生了Ca^2+依赖性节律性Cl^-电流，节律性电流被认为是胃肠起搏器的起源。药物引起的收缩的异常程度与药物引起的收缩的程度相关。当对照动物的胃肠段灌注低温器官浴溶液时，模仿了 ACK2 处理动物的制剂中的异常药物诱导收缩，并伴有节律性收缩受损。这些结果表明，由c-kit细胞的节律性兴奋输入触发的平滑肌细胞的节律性兴奋放电调节药物诱导的收缩程度。 α_1-酸性糖蛋白在用去氧肾上腺素预收缩的小鼠主动脉中产生短暂的松弛，更可能的是α_1-酸性糖蛋白诱导的松弛是由于平滑肌中Ca ^ 2+ -进入的阻断。 α_1-酸性糖蛋白引起的短暂舒张可能会随着外周血管的长期舒张而发生，这可能会导致血液的改善。炎症组织的循环较少。