MECHANISMS OF NEUTROPHIL MARGINATION IN THE NORMAL LUNG

由于未知原因，循环中超过一半的中性粒细胞 通常情况下，边缘位于肺部。作为宿主免疫防御的一部分，这些 细胞可以释放多种有效的分泌产物来杀死入侵 微生物。虽然这种破坏性的潜力通常是可以控制的 并保护宿主，中性粒细胞也可损伤微血管 内皮，产生更高的血管通透性，最终 成人呼吸窘迫综合征伴随高发病率和 死亡率。中性粒细胞不可避免地出现在 肺血管渗漏引起了调查人员的注意 正常情况下导致中性粒细胞优先边集的机制 肺循环。目前，两个假设正在接受测试。 首先，机械障碍假说，缓慢变形， 球形中性粒细胞(与高度柔韧的盘状 红细胞)被认为是机械障碍，因为它们遇到 毛细管床中狭窄的地方。第二，粘着性 假说，据推测，中性粒细胞表面的一个 黏附促进分子，在炎症过程中如此重要， 与肺血管内皮细胞相互作用导致一过性停搏 中性粒细胞，从而形成边际池。因为 直接研究肺微循环的困难， 关于肺中性粒细胞动力学的几乎所有方面的细节， 包括正常边际作用的重要机制，目前仍不清楚。 为了直接研究这些过程，我们进行了微观观察。 活肺，这是我们实验室独有的技术。我们有 确定了大多数中性粒细胞通常在 散布在密集的毛细血管网络中的离散位置 就像在第二个，数量上不那么重要的隔室，沿着静脉 内皮细胞。我们现在建议在体内进行进一步的研究。 显微镜和技术改变中性粒细胞变形性或 坚持回答以下问题。是什么导致中性粒细胞 毛细血管停滞：机械障碍还是粘合剂相互作用？做 毛细管床中的几何因素，如众多 毛细管间连接、单个管段直径或 个别节段扩张，在中性粒细胞转运中起作用？做 中性粒细胞通过黏附在小静脉中形成边缘，如果是这样的话 中性粒细胞黏附分子？是中性粒细胞黏附的改变还是 中性粒细胞边际增多的力学特性 对血管内刺激的反应？两者之间的关系是什么？ 中性粒细胞边际化和中性粒细胞迁出的机制 发炎的部位？移民发生在什么地方： 毛细血管还是小静脉？这些研究，特别集中在角色 中性粒细胞在肺内皮细胞相互作用中的作用 微循环，将成为我们之间独特而重要的桥梁 对中性粒细胞分子决定因素的认识不断加深 体外功能与更经典的整体器官生理学研究 这往往为解决重要的临床问题指明了方向。

For unknown reasons, more than half of the neutrophils in the circulation normally marginate in the lungs. As part of host immune defense, these cells can release a variety of potent secretory products to kill invading microorganisms. While this destructive potential is usually controlled and protects the host, neutrophils can also injure the microvascular endothelium, producing increased vascular permeability and ultimately adult respiratory distress syndrome with high attendant morbidity and mortality. The inevitable presence of neutrophils at the site of pulmonary vascular leak has drawn investigative attention to the mechanisms that normally cause neutrophils to marginate preferentially in the pulmonary circulation. Currently, two hypotheses are being tested. In the first, the mechanical impediment hypothesis, the slowly deforming, spherical-shaped neutrophils (compared to the high flexible, disc-shaped red blood cells) are thought to be mechanically impeded as they encounter narrow places in the capillary bed. In the second, the adhesion hypothesis, it is postulated that one of the neutrophil cell surface adhesion-promoting molecules, so important in inflammatory processes, interact with the pulmonary vascular endothelium to cause transient arrest of the neutrophils thereby forming the marginated pool. Because of the difficulty of studying the pulmonary microcirculation directly, the details about virtually all aspects of pulmonary neutrophil kinetics, including the important mechanisms of normal margination, remain obscure. To study these processes directly, we have made microscopic observations of the living lung, a technique unique to our laboratory. We have established that the majority of neutrophils normally marginate at discrete sites scattered throughout the dense capillary network, as well as in a second, quantitatively less important compartment, along venular endothelium. We now propose further investigations using in vivo microscopy and techniques to alter either neutrophil deformability or adhesion to answer the following questions. What causes neutrophils to stop in capillaries: mechanical impediments or adhesive interactions? Do geometric factors in the capillary bed, such as the numerous intercapillary junctions, individual segment diameter, or the capacity of individual segments to dilate, play a role in neutrophil transit? Do neutrophils marginate in venules by adhesion, and if so by which neutrophil adhesion molecules? Are changes in neutrophil adhesion or mechanical properties responsible for increased neutrophil margination in response to intravascular stimuli? What is the relationship between the mechanisms which cause neutrophil margination and neutrophil emigration at sites of inflammation? From what location does emigration occur: capillaries or venules? These studies, specifically focused on the role of the neutrophil in neutrophil-endothelial interactions in the pulmonary microcirculation, will serve as a unique and important bridge between our increasing understanding of the molecular determinants of neutrophil function in vitro and the more classical study of whole organ physiology which so often points the way to solving important clinical problems.