Building a Better Neosquamous Barrier

巴雷特食道(BE)是一种特殊的柱状上皮，进展为食道 腺癌(EAC)以每年约0.5%的速度增长。预防癌症的一个策略是内窥镜消融术。加了酸 通过质子泵抑制剂(PPI)的抑制，消融会导致(NEO)鳞状结构取代Be 上皮细胞(NSE)。为了使这一方法取得成功，NSE必须成为防止复发的持久、有效的障碍 因反流造成的损伤。NSE的持久性尚不确定。Ar等离子体凝固的消融缺乏耐久性， BE复发率高达66%。此外，最近的数据表明，在接受治疗的人中，有25% 射频消融术(RFA)术后1年复发。此外，我们发现了有缺陷的证据 在RFA之后出现的NSE障碍。这种缺陷类似于在自然鳞状组织中观察到的 格尔德。具体地说，NSE表现为细胞间隙扩张，功能上具有低电阻 以及对荧光素的高(细胞旁)渗透性。这些异常都表明交界处有缺陷。 障碍-在治疗后和接受PPI期间持续长达2年的障碍。此外，我们发现NSE具有较低的 Claudin-4，一种紧密连接的异常，可能是屏障功能受损的原因。我们有 在细胞培养中显示，用类黄酮类化合物--栎素处理后，Claudin-4的表达增加 和改进的屏障功能。因此，我们假设NSE中的缺陷壁垒是由低 这一缺陷增加了对H+的通透性，并促进了对NSE的反复反流损伤。我们 此外，还假设Quercetin上调claudin-4将改善屏障功能并减少 NSE的脆弱性。

Barrett's esophagus (BE), a specialized columnar epithelium, progresses to esophageal adenocarcinoma (EAC) at a rate of ~0.5%/yr. One strategy to prevent cancer is endoscopic ablation. With acid suppression by proton pump inhibitors (PPIs), ablation results in the replacement of BE by (neo)squamous epithelium (NSE). For this approach to be successful, the NSE must be a durable, effective barrier to recurrent injury from reflux. The durability of NSE is uncertain. Ablation by argon plasma coagulation lacks durability,with re-emergence of BE in up to 66% pts. Additionally, recent data suggest that 25% of those undergoing radiofrequency ablation (RFA) had recurrent disease at 1 yr. Moreover, we found evidence of a defective barrier in NSE that emerged following RFA. This defect is similar to that observed in native squamous tissue in GERD. Specifically, NSE exhibited dilated intercellular spaces and functionally had low electrical resistance and high (paracellular) permeability to fluorescein. These abnormalities all indicate a defect in the junctional barrier - one that persists for up to 2 yrs after therapy and while on PPIs. Further, we found that NSE had low claudin-4, an abnormality of the tight junction that could account for impairment in barrier function. We have shown in cell culture that treatment with a flavanoid, Quercetin, resulted in both increased claudin-4 expression and improved barrier function. Therefore, we hypothesize that the defective barrier in NSE results from low claudin-4 and that this defect increases permeability to H+ and promotes recurrent reflux damage to NSE. We also hypothesize that upregulation of claudin-4 by Quercetin will improve barrier function and reduce the vulnerability of NSE.