Venular leukocyte adhesion, impaired arteriolar vasoreactivity, and intestinal IR

小静脉白细胞粘附、小动脉血管反应性受损和肠道 IR

• 批准号: 7752528
• 负责人: RONALD JOHN KORTHUIS
• 金额: $ 37.03万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-22 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752528
• 关键词: Accounting; Acetylcholine; Address; Adherence; Adhesions; Adhesives; Angiotensin II; Animal Model; Animals; Antioxidants; Arteries; Biological Availability; Blood Vessels; Blood flow; Cell Adhesion Molecules; Cell Degranulation; Chymase; Coupling; Data; Development; Emigrations; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Event; Exhibits; Extravasation; Functional disorder; Gelatinase B; Genes; Infiltration; Intercellular adhesion molecule 1; Intestines; Ischemia; Ischemic Bowel Disease; Laboratories; Leukocyte Rolling; Leukocytes; Link; Mediating; Mesentery; Microscopic; Modeling; Mus; Nitric Oxide; Organ; Oxidases; P-Selectin; Pathogenesis; Pathology; Peptide Hydrolases; Permeability; Play; Reaction; Reactive Oxygen Species; Reagent; Relaxation; Reperfusion Therapy; Role; Shock; Signal Transduction; Small Intestines; Stimulus; Superoxide Dismutase; Superoxides; Testing; Tissues; Vasodilation; Work; arteriole; knockout animal; mast cell; novel; postcapillary venule; prevent; response

DESCRIPTION (provided by applicant): One of the earliest events in the pathogenesis of intestinal ischemia/reperfusion (I/R) is microvascular dysfunction that is characterized by leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated vasodilatory responses (EDO) in upstream arteries and arterioles. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that I/R- induced LECA in postcapillary venules is causally linked to EDO dysfunction in arterioles. However, the mechanisms coupling l/R-induced LECA in postcapillary venules and postischemic EDO dysfunction in upstream arterioles are unknown. Our overall hypothesis is that l/R-induced EDO dysfunction in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes that induce mast cell-dependent formation of angiotensin II. Subsequent activation of NAD(P)H oxidase in the vascular wall leads to the formation of reactive oxygen species which inactivates NO, thereby impairing EDO in arterioles. We will test this hypothesis by determining: 1) whether LECA in postcapillary venules play an obligatory role in the development of EDO in upstream arterioles; 2) the contribution of leukocyte-derived proteases (eg, matrix metalloproteinase-9 (MMP-9)) to EDO in arterioles; and 3) whether EDO dysfunction in arterioles is due to mast cell-derived chymase-dependent formation of All. Intravital microscopic approaches will be used to examine arteriolar EDO, venular LECA, and mast cell responses to I/R. A number of gene knockout animal models (P-selectin-/-, CD11/CD18-/-, ICAM-1-/-, MMP-9-/-, mast cell-deficient mice) will be used to further explore the mechanisms of impaired EDO arterioles isolated from postischemic intestine. Collectively, these aims address a novel mechanism to explain the profound disturbance in, arteriolar vasoregulatory function in tissues subjected to I/R. This work will identify new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, and EDO dysfunction in arterioles. Given the importance of the endothelium in regulating vascular tone, these fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.

DESCRIPTION (provided by applicant): One of the earliest events in the pathogenesis of intestinal ischemia/reperfusion (I/R) is microvascular dysfunction that is characterized by leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated vasodilatory responses (EDO) in upstream arteries and小动脉。即使白细胞在牙齿后肠道中没有沿着动脉内皮循环，粘附或移民，但最近的工作表明，后毛细血管后静脉内的I/r-诱导的LECA与动脉中的edo eDO功能障碍有关。然而，在毛细血管后静脉中偶联的L/R诱导的LECA的机制以及上游小动脉中缺血后的江户功能障碍尚不清楚。我们的总体假设是，L/R诱导的小动脉中的EDO功能障碍是通过一种机制发生的，该机制是由LECA在后毛细血管后静脉触发的机制发生的，并涉及由迁移的白细胞蛋白水解活性引起的信号的形成，从而诱导乳腺细胞的蛋白水解活性，从而引起Mast Cell依赖性依赖性依赖性依赖性的依赖型乳腺细胞。随后在血管壁中NAD（P）H氧化酶的激活导致反应性氧的形成，而反应性氧，从而使NO失活，从而损害了小动脉中的EDO。我们将通过确定：1）毛细血管后静脉内的leca是否在上游小动脉的江户发展中起着强制性作用； 2）白细胞衍生的蛋白酶（例如，基质金属蛋白酶9（MMP-9））对小动脉中的EDO的贡献； 3）小动脉中的江户功能障碍是否是由于肥大细胞衍生的全伴侣依赖性的形成。插入性微观方法将用于检查动脉江户，静脉LECA和肥大细胞对I/R的反应。许多基因基因敲除动物模型（P-选择素 - ，CD11/CD18 - / - ，ICAM-1-/ - ，MMP-9 - / - ，肥大细胞缺陷型小鼠）将用于进一步探索与美食后的遗传学分离的受损的edo动脉动脉的机制。总的来说，这些目的介绍了一种新的机制来解释受I/R的组织中的动脉血管调节功能的深刻干扰。这项工作将确定后毛细血管静脉静脉内的LECA之间的新联系，在迁移的白细胞中在间质中产生的信号以及小动脉功能障碍。鉴于内皮在调节血管张力方面的重要性，这些根本重要的发现对我们对I/R的条件下对血液流量失调的理解具有巨大的影响。