T-Type Calcium Channels and Neutrophil Transmigration

进入肺泡的病原体和有害物质会引发炎症反应，即 特点是中性粒细胞从循环中重新聚集到主循环中。中性粒细胞 最初通过毛细血管内皮细胞进入肺泡，因此，这些 微血管内皮细胞具有把关功能。而在正常情况下，未燃烧 毛细血管内皮细胞不损害中性粒细胞通过毛细血管的运动 毛细血管内皮细胞对炎症反应迅速诱导表面P-受体表达 选择素，它与中性粒细胞相互作用，启动中性粒细胞向肺泡的迁移。增加了…… 内皮细胞胞浆钙促进含P-选择素的囊泡移位 从细胞质溶质到质膜。我们最近的证据表明QIGT型钙通道 提供这种P-选择素表面表达所需的胞内钙源； 钙通道仅在毛细血管内皮细胞中表达，而在肺动脉和肺组织中均不表达 静脉内皮细胞在肺微循环中发挥着高度专门化的作用。的确， 我们的初步数据显示，铜绿假单胞菌可引起严重的中性粒细胞募集 通常，这种效应在QIG和P-选择素基因敲除小鼠中被取消。目前， 调节P-选择素表面表达和中性粒细胞的钙反应事件 轮回仍然鲜为人知。值得注意的是，我们的初步数据表明QIG T 型钙通道与内皮细胞一氧化氮合酶(N0S3)相互作用。钙 通过QIG通道的渗透激活了N0S3，N0S3产生了对抗P的一氧化氮 选择素的表面表达，反馈调节的特点。因此，这一行动的具体目的是 项目将测试在肺泡毛细血管内皮细胞中的假设：[1]QIG与N0S3相关 并控制其激活；[2]N0S3衍生的一氧化氮抑制P-选择素的胞吐；以及[3]QIG 诱导的N0S3激活限制了内皮细胞向促炎表型的转变 总而言之，本项目将确定QIG T-型钙通道和N0S3是否代表 调节急性肺损伤中性粒细胞转运的新治疗靶点。 相关性(请参阅说明)： 中性粒细胞是抵抗感染所需的白细胞。当病原体，如细菌， 进入主干道后，中性粒细胞从血液中迁移到主干道中。这个中性粒细胞 反应受到高度控制，以确保不会招募太多或太少的细胞 中性粒细胞气道募集的机制目前知之甚少，一直是研究的焦点。 我们的研究成果。

Pathogens and noxious agents that access the alveoli initiate an inflammatory response that is characterized by neutrophil recruitment out of the circulation and into the ainways. Neutrophils initially transmigrate across capillary endothelium to access the alveoli, and hence, these microvascular endothelial cells possess a gatekeeper function. Whereas under normal, un-lnflamed conditions capillary endothelium does not Impair neutrophil movement through capillaries, in response to inflammation capillary endothelium promptly induces the surface expression of P- selectin, which interacts with neutrophils and initiates their transmigration into alveoli. An increase in endothelial cell cytosolic calcium promotes the translocation of vesicles containing P-selectin from the cytosol to the plasma membrane. Our recent evidence indicates the QIG T-type calcium channel provides the cytosolic calcium source that is needed for such P-selectin surface expression; as this calcium channel Is only expressed in capillary endothelium, and not in either pulmonary artery or vein endothelium, it appears to fulfill a highly specialized role in the lung microcirculation. Indeed, our preliminary data reveal that Pseudomonas aeruginosa causes profound neutrophil recruitment to the ainways, an effect that is abolished in QIG and P-selectin knockout mice. At present, the calcium responsive events that modulate P-selectin surface expression and neutrophil transmigration remain poorly understood. Notably, our preliminary data demonstrate that the QIG T type calcium channel interacts with endothelial cell nitric oxide synthase (N0S3). Calcium permeation through the QIG channel activates N0S3, which produces nitric oxide that opposes P selectin surface expression, characteristic of feedback regulation. Hence, the Specific Aims of this project will test the hypotheses that in alveolar capillary endothelium: [1] QIG associates with N0S3 and controls its activation; [2] N0S3-derived nitric oxide inhibits P-selectin exocytosis; and [3] QIG induced N0S3 activation limits the endothelial transition to a proinflammatory phenotype Collectively, this project will determine whether the QIG T-type calcium channel and N0S3 represent novel therapeutic targets for the regulation of neutrophil trafficking in acute lung injury. RELEVANCE (See instructions): Neutrophils are white blood cells that are needed to fight infection. When pathogens, like bacteria, access the ainways, neutrophils migrate out of the blood and into the ainways. This neutrophil response is highly regulated, to ensure that neither too many nor too few cells are recruited Mechanisms responsible for neutrophil airway recruitment are poorly understood, and are the focus of our studies.