Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease

定义 Fontan 姑息治疗或炎症性肠道疾病后蛋白质丢失性肠病的淋巴基础

• 批准号: 10325733
• 负责人: Gwendalyn J Randolph
• 金额: $ 78.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10325733
• 关键词: Affect; Blood; Blood Circulation; Blood Vessels; Budesonide; Child; Common Ventricle; Complication; Crohn' s disease; Disease; Epithelial; Epithelial Cells; Etiology; Experimental Animal Model; Failure; Functional Imaging; Heart; Heart Ventricle; Human; Inflammatory; Intercellular Junctions; Intestines; Lamina Propria; Life; Link; Liquid substance; Literature; Lung; Lymph; Lymphatic; Lymphatic System; Mesentery; Modeling; Participant; Pathologic; Patients; Procedures; Protein-Losing Enteropathies; Proteins; Research; Role; Savings; Signal Transduction; Steroids; Testing; Tissues; Venous system; clinically significant; improved; intestinal barrier; intestinal epithelium; lymph flow; lymphatic circulation; lymphatic dysfunction; lymphatic valve; lymphatic vasculature; mortality; negative affect; novel strategies; palliation; pressure; stem

ABSTRACT Protein-losing enteropathy (PLE) is the term given to the pathological phenomenon of protein dumping from the systemic circulation into the intestinal lumen. Various degrees of PLE are observed in a variety of otherwise unrelated diseases. For instance, PLE is a complication of the life-saving Fontan palliation procedure performed on children born with only a single ventricle of the heart to create a vascular diversion to the lungs to promote improved oxygenation of blood. Fontan-associated PLE is linked with high mortality: 30-50% over 5- to 10-years. Yet, PLE remains understudied. The dominant causal mechanisms underlying PLE appear to relate to (1) loss of barrier integrity at the intestinal epithelium or (2) functional disturbance of the lymphatic vasculature. Intestinal epithelial cell erosion would expose proteinaceous tissue fluid to the intestinal lumen. Furthermore, poor epithelial intercellular junctions might allow for the contents of the lamina propria interstitium to leak into the intestinal lumen. With respect to lymphatics, failure of lymph to flow away from the intestine uni-directionally toward the heart and instead to flow backwards from the body trunk toward the intestine with sufficient force to break across the epithelium may be a major cause of PLE. The literature presents Fontan palliation-associated PLE as a problem driven by lymphatic backflow, whereas PLE in IBD (such as Crohn's disease) is presented as being of mixed etiology that involves breach of epithelial integrity with possible additional contributions stemming from lymphatic dysfunction. However, it is acknowledged in the literature that the full basis of PLE in any of these conditions is uncertain and that there are several reasons why the current explanations may be questioned. We will carry out focused research on PLE that includes studies involving human participants as well as studies in experimental animal models. Our hypotheses are, first, that the lymphatic vasculature is a primary player in PLE affecting Fontan patients and IBD patients, and second, that the lymphatic vasculature must receive “two hits” to drive sufficient backflow of lymph to cause outflow from the intestinal barrier. The first of these hits has already been considered (but not completely tested) in the context of Fontan palliation: increased pressure within the chain of lymphangions (vessel units between lymphatic valves). We propose this second hit is an inflammatory signal that negatively affects lymphatic valves. The two-hit model may resolve a confusing observation in Fontan patients with PLE wherein treatments with steroids like budesonide can be effective. A steroid seems unlikely to strongly alter pressure in the venous and lymphatic systems, but it is easy to envision how steroids may help by reducing adverse inflammatory signalling associated with valve failure. If this model is correct, a path to therapies not previously considered to treat PLE may become evident.

抽象的 蛋白质失去的肠病（PLE）是赋予蛋白质倾倒的病理现象的术语 全身圆进入肠腔。在各种否则中观察到各种程度的PLE 无关的疾病。例如，PLE是执行挽救生命的Fontan palliation程序的并发症 关于只有心脏通风的孩子，可以为肺部引起血管转移以促进 改善血液氧合。 Fontan相关的PLE与高死亡率相关：5至10年以上的30-50％。 但是，PLE仍然是被理解的。 PLE背后的主要因果机制似乎与（1）损失有关 肠上皮上的屏障完整性或（2）淋巴管的功能性灾难。 上皮细胞侵蚀将使蛋白质组织液暴露于肠腔。此外，贫穷 上皮间接口可能允许固有层间质层的内容物泄漏到 肠腔。关于淋巴机，淋巴在肠道上失败 朝着心脏，而是用足够的力从身体躯干向后流向肠子 在上皮上破裂可能是PLE的主要原因。文献介绍了Fontan palliation相关的 PLE是由淋巴回流驱动的问题 成为混合病因，涉及违反上皮完整性，并可能采取其他贡献 来自淋巴功能障碍。但是，在文献中承认，PLE在其中任何一个中的全部基础 条件是不确定的，并且可能会质疑当前的解释有几个原因。我们 将对PLE进行重点研究，其中包括涉及人类参与者的研究以及研究 实验动物模型。首先，我们的假设是淋巴脉管系统是PLE的主要参与者 影响丰丹患者和IBD患者，其次，淋巴管系统必须获得“两次命中” 驱动足够的淋巴回流以引起肠屏障的出口。这些命中中的第一个已经 在fontan palliation的背景下考虑（但未完全测试）： 淋巴管链（淋巴瓣之间的血管单位）。我们提出第二次命中是一种炎症 信号对淋巴瓣负面影响。两次打击的模型可能会解决方坦的混乱观察 PLE患者使用类固醇（如布德索尼）治疗的患者可以有效。类固醇似乎不太可能 强烈改变静脉和淋巴系统的压力，但是很容易设想类固醇如何帮助 减少与瓣膜故障相关的不良炎症信号传导。如果此模型正确，则是治疗途径 以前不认为治疗PLE可能成为证据。