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

研究表明，中枢神经系统疾病引起的交感神经过度兴奋可介导神经源性肺水肿。但确切的机制仍然未知。在本研究中，我们得到了以下结果.将纤维蛋白原和凝血酶注射到大鼠的小脑延髓池中诱导NPE（纤维蛋白诱导的肺水肿：FIPE）。采用酶联免疫法测定神经肽Y（NPY）。NPY在FAPE的肺泡巨噬细胞和水肿液中被发现，但在流体静力性水肿中几乎不存在。药理学研究发现，NPY Y_3受体与肺血管通透性有关.通过使用大鼠内皮细胞（RAEC）单层培养物，测定内皮通透性。NPY不影响周围空气中培养的RAEC的通透性，但在低氧条件下（5%氧），增加通透性的剂量依赖性。药理学研究表明REAC的Y_3受体与缺氧条件下通透性的增加有关.据报道，一氧化氮（NO）在中枢神经系统和外周组织中具有不同的作用，与肺水肿的发生有关。在FIPE中，在迷走神经完整的大鼠脑4侧脑室注射NO抑制剂<th>可加速肺水肿的发展，但在迷走神经切断后则无明显变化。注射精氨酸后，迷走神经完整大鼠的NPE无明显变化，而迷走神经切断大鼠的NPE明显降低.单侧迷走神经切断对FIPE的抑制作用与孤束核脑内一氧化氮合酶（bNOS）水平升高有关.延髓中的L-谷氨酸可通过促进NO的合成而抑制NPE的发生，目前我们正在克隆NPYY_3受体，这将极大地促进治疗NPE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.