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

摘要 蛋白质丢失性肠病(PLE)是指蛋白质从肠外排出的病理现象。 进入肠腔的体循环。不同程度的PLE在不同的其他方面都可以观察到 无关的疾病。例如，PLE是Fontan姑息治疗过程中的并发症 对出生时只有一个脑室的儿童的心脏进行血管分流以促进肺部 改善血液的氧合。与方坦相关的PLE与高死亡率有关：5至10年内死亡率为30-50%。 然而，对PLE的研究仍然很少。支持PLE的主要原因机制似乎与(1)损失有关 肠上皮屏障完整性或(2)淋巴管系统功能障碍。肠道 上皮细胞侵蚀会使蛋白质组织液暴露在肠腔内。此外，穷人 上皮细胞间连接可能允许固有层间质的内容物渗入 肠腔。淋巴管方面，淋巴不能从肠道单向流出 并以足够的力量从躯干向后流向肠道 穿透上皮可能是PLE的主要原因。文献介绍了与方坦姑息相关的 淋巴管回流导致的PLE，而IBD(如克罗恩病)的PLE表现为 混合病因学，涉及上皮完整性的破坏，可能有额外的贡献 淋巴功能障碍。然而，文献中承认，在任何一种情况下，PLE的全部基础 情况是不确定的，有几个原因可能会对目前的解释提出质疑。我们 将对PLE进行重点研究，包括涉及人类参与者的研究以及 实验动物模型。我们的假设是，首先，淋巴管系统是PLE的主要参与者 影响Fontan患者和IBD患者，第二，淋巴管系统必须接受两次打击 驱动足够的淋巴回流，使之从肠道屏障流出。这些热门歌曲中的第一个已经 在Fontan姑息疗法的背景下被考虑(但未完全测试)：在 淋巴管链(淋巴瓣之间的血管单位)。我们认为这第二次袭击是一次煽动性的 对淋巴瓣有负面影响的信号。两次命中模型可能会解决方坦的一个令人困惑的观察结果 患有PLE的患者，使用布地奈德等类固醇治疗可能有效。类固醇似乎不太可能 强烈改变静脉和淋巴系统的压力，但很容易想象类固醇如何通过 减少与瓣膜衰竭相关的不良炎症信号。如果这个模型是正确的，一条通往治疗的道路 以前没有被认为可以治疗PLE的情况可能会变得明显。

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.