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 蛋白质丢失性肠病（PLE）是指蛋白质从肠道倾倒的病理现象。 在各种其他情况下都观察到不同程度的全身性 PLE。 例如，PLE 是挽救生命的 Fontan 姑息手术的并发症。 对出生时只有一个心室的儿童进行血管分流至肺部以促进 Fontan 相关的 PLE 的血液氧合改善与高死亡率有关：5 至 10 年内死亡率高达 30-50%。 然而，PLE 的主要因果机制似乎与 (1) 损失有关。 肠上皮屏障完整性的破坏或（2）淋巴管系统的功能障碍。 上皮细胞侵蚀会使蛋白质组织液暴露于肠腔。 上皮细胞间连接可能允许固有层间质的内容物渗漏到 就淋巴管而言，淋巴管无法单向流出肠道。 流向心脏，而不是以足够的力量从身体躯干向后流向肠道 突破上皮可能是 PLE 的主要原因，文献提出与 Fontan 姑息治疗相关。 PLE 是由淋巴回流驱动的问题，而 IBD（如克罗恩病）中的 PLE 则表现为 具有混合病因，涉及上皮完整性的破坏，并可能造成其他影响 然而，文献承认 PLE 的全部基础在于这些。 情况是不确定的，目前的解释可能受到质疑的原因有几个。 将针对 PLE 开展重点研究，包括涉及人类参与者的研究以及以下方面的研究 首先，我们的假设是淋巴管系统是 PLE 的主要参与者。 影响 Fontan 患者和 IBD 患者，其次，淋巴管系统必须受到“两次打击” 驱动足够的淋巴液回流，导致肠道屏障流出。 在 Fontan 姑息治疗的背景下被考虑（但尚未完全测试）：体内压力增加 我们认为第二次打击是炎症。 对淋巴瓣膜产生负面影响的信号，两次击打模型可能会解决 Fontan 中令人困惑的观察结果。 PLE 患者使用布地奈德等类固醇治疗似乎不太可能有效。 强烈改变静脉和淋巴系统的压力，但很容易想象类固醇如何通过以下方式提供帮助： 减少与瓣膜衰竭相关的不良炎症信号如果该模型正确，这是一条治疗途径。 以前没有考虑过治疗 PLE 的可能会变得明显。