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

摘要 蛋白丢失性肠病（PLE）是指蛋白质从肠道排出的病理现象。 体循环进入肠腔。不同程度的PLE被观察到在各种其他 不相关的疾病。例如，PLE是一个并发症的救生丰唐姑息程序进行 对出生时只有一个心室的孩子，以创造一个血管转移到肺部， 改善血液的氧合。Fontan相关的PLE与高死亡率有关：5至10年内为30 - 50%。 然而，PLE仍然研究不足。PLE的主要因果机制似乎与（1）损失 肠上皮屏障完整性或（2）淋巴管系统功能紊乱。肠 上皮细胞侵蚀将使蛋白质组织液暴露于肠腔。此外，穷人 上皮细胞间连接可能允许固有层的内容物渗漏到 肠腔淋巴液不能从肠道单向流出， 相反，它会以足够的力量从身体躯干流向肠道， 上皮破裂可能是PLE的主要原因。文献显示Fontan姑息相关 PLE是由淋巴回流引起的问题，而IBD（如克罗恩病）中的PLE则表现为 具有混合病因，涉及破坏上皮完整性，可能有其他贡献， 淋巴功能紊乱然而，在文献中承认，在这些文献中的任何一个中的PLE的全部基础都是不可靠的。 他说，情况是不确定的，有几个原因可以质疑目前的解释。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，第一，淋巴管系统是一个主要的球员在PLE 影响Fontan患者和IBD患者，第二，淋巴管系统必须接受"两次打击" 以驱动足够的淋巴回流，从而导致从肠屏障流出。第一次袭击已经 在Fontan缓解的背景下考虑（但未完全测试）： 淋巴管链（淋巴管瓣之间的血管单位）。我们认为第二次袭击是一次煽动性的袭击 对淋巴阀有负面影响的信号。两次打击模型可以解决Fontan中令人困惑的观察结果 其中使用类固醇如布地奈德治疗可能有效的PLE患者。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传导。如果这个模型是正确的， 以前没有考虑过的治疗PLE的方法可能变得明显。

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.