Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function
Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function
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DOI：
10.1172/jci32335
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Freeze, Hudson H.
中科院分区：
文献类型：
--
作者：
Bode, Lars;Salvestrini, Camilla;Freeze, Hudson H.
患有蛋白丢失性肠病（PLE）的患者不能维持肠上皮屏障功能，并产生过量且可能致命的血浆蛋白外排。PLE发生在表面上不相关的疾病，但在临床观察中出现的共性最近使我们确定PLE发病机制的关键球员。这些包括升高的IFN-γ、TNF-α、静脉高压和来自肠基底外侧表面的硫酸乙酰肝素蛋白聚糖的特异性损失。上皮细胞在PLE发作期间。这里我们展示的是肝素。硫酸乙酰肝素和syndecan-1（主要的肠上皮硫酸乙酰肝素蛋白聚糖）在维持肠上皮屏障功能中是必需的。硫酸乙酰肝素或syndecan-1缺陷小鼠和硫酸乙酰肝素膀胱特异性丢失的小鼠基础蛋白渗漏增加，并且更容易受到IFN-γ、TNF-α和静脉压升高联合诱导的蛋白丢失的影响。类似地，在人上皮细胞中多配体蛋白聚糖-1的敲低导致增加的基础和甘氨酸诱导的蛋白质渗漏。肝素的临床应用已被认为可以缓解某些患者的PLE，但其机制不明，以及由于其抗凝活性而导致的严重副作用限制了其实用性。我们在这里证明，非抗凝剂2，3-去氧硫酸肝素可以防止syndecan缺陷小鼠的肠蛋白渗漏，这表明这可能是一种安全有效的治疗PLE患者。
Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal. epithelial cells during PLE episodes. Here we show that heparan. sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-l-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.