Lung/renal interactions in VALI

VALI 中的肺/肾相互作用

• 批准号: 6820147
• 负责人: HAMID RABB
• 金额: $ 21.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820147
• 关键词: acute renal failure; adult respiratory distress syndrome; biological fluid transport; comorbidity; dogs; histopathology; inflammation; intensive care; laboratory mouse; leukocyte adhesion molecules; pathologic process; respirators; respiratory airway volume; selectins; vascular endothelium permeability

Acute renal failure (ARF) is associated with a 40% mortality rate in the ICU, while acute lung injury (ALl) is associated with a 35% mortality. ARF and ALl frequently co-exist, and when this occurs, the mortality rate is 80%. Despite this frustrating outcome, little is known about the relationships between ARF and VALI. Recent studies from our team demonstrate that ARF directly contributes to lung dysfunction. We have found that lungs in experimental ARF had a marked increase in microvascular inflammation, pulmonary vascular permeability, and dysregulation of transporters implicated in lung edema clearance. In turn, it has been known for many years that mechanical ventilation can independently lead to changes in renal function. Preliminary data from our group has demonstrated that injurious mechanical ventilation may influence the systemic inflammatory response by leading to upregulation of intra-renal cytokines and adhesion molecules, which are putative mediators in the development of ARF. Based on these data, we hypothesize that ARF predisposes to VALI, and that in turn, VALI predisposes to ARF. We hypothesize that high volume ventilation directly contributes to the systemic inflammatory response manifest in the kidneys, and that inflammatory pathways mediated by leukocytes and leukocyte adhesion molecules are important mechanisms underlying the links between VALI and ARF. We will test these hypotheses using established murine models of ARF and ALl. Aim 1. Determine the effects of ARF on the lung: histology, function, inflammation, expression of fluid and electrolyte transporters, and gene expression. Aim 2. Test the hypothesis that ARF predisposes the lung to the injurious effects of high tidal volumes and hydrochloric acid. Aim 3. Evaluate the effects of VALI on the kidney. Kidney histology, function, inflammation, and fluid and electrolyte transporters will be assessed. For each of these three aims, we will test the hypothesis that the lung-kidney links are mediated by leukocyte adhesion molecules, and intervene in the CD18-1CAM-1 and selectin pathway. Genomic and proteomic techniques will be used to generate mechanistic hypotheses about pathways mediating ARF/VALI interactions. Close cooperation with histology and biomarker cores will be performed to measure endpoints. The canine core will delineate the hemodynamic and biomechanical aspects of mechanical ventilation effects on kidney. Collaboration on renal outcomes will be undertaken with Project 4 examining endothelial integrity and interventions, and Project 6 regarding effects of hyperoxia. The proposed studies will lead to a better understanding of ARF/VALI interactions and hopefully lead to new therapies.

急性肾衰竭（ARF）与ICU中40%的死亡率相关，而急性肺损伤（AL 1）与35%的死亡率相关。ARF和AL 1经常共存，并且当这种情况发生时，死亡率为80%。尽管这一令人沮丧的结果，很少有人知道ARF和VALI之间的关系。我们团队最近的研究表明，ARF直接导致肺功能障碍。我们发现实验性ARF的肺微血管炎症、肺血管通透性和与肺水肿清除有关的转运蛋白调节异常显著增加。反过来，多年来人们已经知道，机械通气可以独立地导致肾功能的变化。 我们小组的初步数据表明，损伤性机械通气可能通过导致肾内细胞因子和粘附分子的上调来影响全身炎症反应，这些细胞因子和粘附分子是ARF发展中的假定介质。基于这些数据，我们假设ARF易患VALI，反过来，VALI易患ARF。我们假设高容量通气直接导致肾脏中的全身炎症反应，并且白细胞和白细胞粘附分子介导的炎症途径是VALI和ARF之间联系的重要机制。我们将使用已建立的ARF小鼠模型来检验这些假设 和ALl。目标1。确定ARF对肺的影响：组织学、功能、炎症、液体和电解质转运蛋白的表达以及基因表达。目标二。检验ARF使肺易受高潮气量和盐酸损害的假设。目标3。评价VALI对肾脏的影响。将评估肾脏组织学、功能、炎症以及液体和电解质转运蛋白。对于这三个目标中的每一个，我们将检验肺-肾联系是由白细胞粘附分子介导的假设，并干预CD 18 -1CAM-1和选择素途径。基因组学和蛋白质组学技术将被用来产生机制假说的途径介导的ARF/VALI的相互作用。将与组织学和生物标志物核心密切合作，以测量终点。犬的核心将描绘血液动力学和生物力学方面的机械通气对肾脏的影响。将与项目4（检查内皮完整性和干预措施）和项目6（关于高氧影响）合作研究肾脏结局。拟议的研究将导致更好地了解ARF/VALI相互作用，并有望导致新的治疗方法。