Study on the Neural Network relating to Pulmonary Vascular Permeability and Cloning of its Receptor

已有研究表明，与中枢神经系统(CNS)疾病相关的交感神经过度活动介导了神经源性肺水肿(NPE)。但确切的机制仍不清楚。在本研究中，我们获得了以下结果。大鼠枕大池注射纤维蛋白原和凝血酶可致大鼠纤维蛋白肺水肿(NPE)。用酶联免疫法测定神经肽Y(NPY)。肺泡巨噬细胞和肺水肿液中可见NPY，而静水肿胀时NPY几乎不存在。药理学研究表明NPY Y_3受体与肺血管通透性有关。采用大鼠内皮细胞(RAEC)单层培养，测定内皮通透性。NPY对环境空气中培养的RAEC通透性无明显影响，但在低氧(5%氧气)条件下可剂量依赖性地增加通透性。药理学研究表明，REAC的Y_3受体与低氧条件下这种通透性增加有关。已有研究表明，一氧化氮(NO)在中枢和外周组织中与肺水肿的发生发展有不同的作用。在FIPE中，在迷走神经完整的情况下，脑室注射NO抑制剂可加速肺水肿的发生，而切断迷走神经时，这种作用不明显。注射精氨酸后，迷走神经完整大鼠的NPE无明显变化，而切断迷走神经的大鼠NPE降低。大鼠左侧迷走神经切断对FIPE的抑制与孤束核脑内一氧化氮合酶(BNOS)水平升高有关。延髓中的L-谷氨酸通过促进NO的合成来抑制NPE。我们目前正在克隆NPY Y_3受体，这将极大地加速治疗NPE的药物的开发。

It has been suggested that sympathetic overactivity associated with central nervous system (CNS) diseases mediates neurogenic pulmonary edema (NPE). But the exact mechanism is still unknown. In this study, we have obtained the following results.1. Fibrinogen and thrombin injected into the cisterna magna of rats induces NPE (fibrin-induced pulmonary edema : FIPE). Neuropeptide Y (NPY) was measured using enzyme-linked immunoassay. NPY was found in the alveolar macrophages and edema fluids in cases of FIPE but was almost absent in hydrostatic edema. Pharmacological studies revealed that NPY Y_3 receptors were found to be associated with pulmonary vascular permeability.2. By using a rat endothelial cell (RAEC) monolayer cultures, endothelial permeability was measured. NPY did not influence permeability of RAEC cultured in the ambient air but increased permeability dose-dependently in hypoxic condition (5% oxygen). Pharmacological studies revealed that Y_3 receptor of REAC was related with this increase in permeability in hypoxic condition.3. It has been reported that nitric oxide (NO) has different effects between CNS and peripheral tissues relating to the development of pulmonary edema. In the FIPE, injection of NO inhibitor in the 4^<th> ventricle of rat brain accelerated the development of pulmonary edema when the vagus nerve was intact, but was unchanged when the vagus was severed. When arginine was injected, NPE was unchanged in the vagus-intact rats, but was decreased in the vagus-severed rats.4. Inhibition of FIPE by previous unilateral left-vagotomy was related with increased levels of brain NO synthase (bNOS) in the nucleus tractus solitarii of rats.5. L-glutamate in the medulla oblongata inhibited NPE by accelerating NO synthesis.We are now in the process of cloning NPY Y_3 receptor, and this will greatly accelerate the development of drugs for the treatment of NPE.