Mechanisms of increased vascular permeability associated with sympathetic excitability and the development of treatment strategy of ARDS.

成人呼吸窘迫综合征（ARDS）等疾病的肺血管通透性增加，其治疗策略至关重要。我们以前曾报道在神经源性肺水肿大鼠中，交感神经中与去甲肾上腺素共存的一种物质（神经肽Y：NPY）具有血管通透性。本研究进一步阐明了NPY与血管通透性的关系。1）Abelson酪氨酸激酶（Abl）与血管通透性Abl是一种与肌动蛋白聚合和核内蛋白合成相关的蛋白磷酸化酶（转录因子）。Abl的非特异性抑制剂可降低由NPY引起的血管通透性。2）NPY与细胞增殖研究表明，血管内皮细胞增殖与血管通透性密切相关。我们已经表明，在高NPY，缺氧增加细胞增殖，而正常的氧浓度引起没有增殖。在低NPY时，缺氧或正常氧浓度均不引起增殖。与增加血管通透性一样，NPY通过蛋白G激活磷脂酶C，激活蛋白激酶C和钙调素依赖性磷酸化酶来促进血管内皮细胞增殖。3）NPY Y_3受体的克隆我们发现，在NPY存在下，缺氧条件下血管内皮细胞增殖的增加与血管通透性增加一样，是通过NPY Y_3受体来实现的。然而，NPY Y_3受体是唯一一个氨基酸序列未知的亚型。在NPYY3受体中，可能存在NPYY2受体的转化。

Diseases such as adult respiratory distress syndrome (ARDS) have increased pulmonary vascular permeability in its entity and treatment strategy is fundamental importance. We have previously reported in the neurogenic pulmonary edema rats that a substance (neuropeptide y: NPY) coexisting with norepinephrine in the sympathetic nerves exerts vascular permeability. We have further elucidated the relationship between NPY and vascular permeability in the present research.1) Abelson tyrosine kinase (Abl) and vascular permeabilityAbl is one of the protein phosphorylation enzymes related with actin polymerization and intranuclear protein synthesis (transcription factor). Non-specific inhibitors of Abl decreased vascular permeability caused by NPY.2) NPY and cell proliferationIt has been reported that vascular endothelial cell proliferation is closely related with vascular permeability. We have shown that in high NPY, hypoxia increased cell proliferation, whereas normal oxygen concentration caused no proliferation. In low NPY, neither hypoxia nor normal oxygen concentration caused proliferation. As in increased vascular permeability, NPY increased vascular cell proliferation by activation of phospholipase C through protein G and activations of protein kinase C and calmodulin-dependent phosphrylation enzyme.3) Cloning of NPY Y_3 receptorWe have found that the increased proliferation of vascular endothelial cells in hypoxia in the presence of NPY was through NPY Y_3 receptor as was found in increased vascular permeability. However, NPY Y_3 receptor is the only subtype of NPY which has unknown amino acids arrangement. In the NPY Y3 receptor, there would be a chance of transformation of the NPY Y_2 receptor.