Physiology of Systemic and Pulmonary Microangiectasias

全身和肺微血管扩张的生理学

• 批准号: 6953170
• 负责人: STEVEN MENTZER
• 金额: $ 33.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953170
• 关键词: blood vessel disorder; cell migration; gastrointestinal circulation; hemodynamics; inflammation; intravital microscopy; laboratory mouse; liver circulation; lymphocyte; mathematical model; microcirculation; morphology; physical model; pulmonary circulation; scanning electron microscopy; skin circulation; three dimensional imaging /topography

DESCRIPTION (provided by applicant): Blood flowing across microvascular endothelium creates shear forces that must be overcome for lymphocytes to transmigrate into perivascular inflammatory tissues. The applicants propose the hypothesis that these forces are overcome by focal structural adaptations in the inflammatory microcirculation. These inflammation-inducible structural changes in the microcirculation-here referred to as microangiectasis-provide a mechanism for the controlled, localized creation of hemodynamic conditions suitable for lymphocyte adhesion and transmigration. Since these conditions must exist wherever lymphocytic inflammation occurs, the applicants propose that comparable structural changes exist in the systemic and pulmonary inflammatory microcirculation. To test these predictions, the applicants propose a combination of structural and functionall studies of microangiectasias in the skin, lung, gut and liver microcirculation. Corrosion casting and 3-dimensional scanning electron microscopy will be used to visualize and quantify the structural morphology of microangiectasias in the inflammatory microcirculation. The functional endpoint of microangiectasias, the transmigration of lymphocytes into extravascular tissues, will be investigated by both tissue cytometry and intravital microscopy. The applicants' preliminary intravital microscopy observation suggest that the motion of lymphocytes in microangiectasias is irregular and disordered; thus, the flow, there may be a recirculating (vortex) flow region in the microangiectasia dominating the motion of migrating cells. To investigate these possibilities, the applicants propose to study the carrier fluid mechanics and the motion of lymphocytes in the microangiectasias using computational fluid dynamic modeling. Finally, the applicants' studies of "normal" lymphocytic inflammation will be extended to a genetically engineered model of focal vascular dilatations. The Endoglin hyploinsufficiency mouse, a model of the human disease hereditary hemorrhagic telangiectasias, demonstrates focal vascular dilatations that appear to be the pathologic manifestation of microangiectasias. The discovery of focal structural adaptations that regulate tissue entry in lymphocytic inflammation has immediate relevance for many areas of vascular biology and adds a new dimension to our understanding of inflammation.

描述（由申请人提供）： 流过微血管内皮的血液会产生剪切力，必须克服淋巴细胞的剪切力才能移民到血管周围炎症组织中。 申请人提出了以下假设：这些力是通过炎症微循环中局灶性结构适应来克服的。 这些微循环中这些炎症诱导的结构变化，被称为微循环，可促进性促进性，是可控的，局部创造的血液动力学条件的机制，适合于淋巴细胞粘附和移民。 由于这些条件必须存在于发生淋巴细胞炎症的任何地方，因此申请人提出在系统性和肺部炎症微循环中存在可比的结构变化。 为了测试这些预测，申请人提出了在皮肤，肺，肠道和肝微循环中微动症的结构和功能研究的结合。 腐蚀铸件和三维扫描电子显微镜将用于可视化和量化炎症微循环中微动症的结构形态。 微动症的功能终点，淋巴细胞的迁移到血管外组织中，将通过组织细胞术和内内显微镜研究。 申请人的初步插入显微镜观察结果表明，微血管紧张病中淋巴细胞的运动是不规则且无序的。因此，流动的流量可能存在循环（涡旋）流动区域，以主导迁移细胞运动的运动。 为了研究这些可能性，申请人建议使用计算流体动力学建模研究载体流体力学和微动淋巴细胞的运动。 最后，申请人对“正常”淋巴细胞炎症的研究将扩展到局部血管扩张的基因工程模型。 内尾型造型小鼠是人类疾病遗传性出血性telangiectasias的模型，表现出局灶性血管扩张，似乎是微型血管菌的病理表现。 发现调节淋巴细胞炎症组织进入组织的局灶性结构适应与许多血管生物学领域的关联，并为我们对炎症的理解增加了新的维度。