Building a Better Neosquamous Barrier

建立更好的新鳞状细胞屏障

• 批准号: 8555514
• 负责人: NICHOLAS J SHAHEEN
• 金额: $ 6.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555514
• 关键词: Ablation; Accounting; Achievement; Acidity; Acids; Argon; Barrett Esophagus; Bile Acids and Salts; Cancerous; Cell Culture Techniques; Coagulation Process; Columnar Epithelium; Data; Defect; Disease; Electrical Resistance; Esophageal Adenocarcinoma; Exhibits; Exposure to; Extracellular Space; Fluorescein; Gastroesophageal reflux disease; Genetic Determinism; Goals; Impairment; In Vitro; Injury; Malignant Neoplasms; Patients; Permeability; Plasma; Proton Pump Inhibitors; Quercetin; Radiofrequency Interstitial Ablation; Recurrence; Recurrent disease; Reflux; Resistance; Risk; Squamous Epithelium; Tight Junctions; Tissues; Up-Regulation; Work; base; claudin 4; flavanoid; improved; in vivo; prevent

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.

巴雷特食管（BE）是一种特化的柱状上皮， 腺癌（EAC）的发病率约为0.5%/年。预防癌症的一种策略是内窥镜消融。用酸 质子泵抑制剂（PPI）抑制，消融导致BE被（新）鳞状上皮替代 上皮细胞（NSE）。为了使这种方法取得成功，NSE必须是一个持久的，有效的屏障， 反流损伤。NSE的持久性是不确定的。氩等离子体凝固消融缺乏耐久性， 高达66%的患者BE复发。此外，最近的数据表明，25%的人接受 射频消融术（RFA）在1年时复发。此外，我们发现了一个有缺陷的 RFA后出现的NSE屏障。这种缺陷类似于在自体鳞状组织中观察到的缺陷。 GERD.具体地说，NSE表现出扩张的细胞间隙和功能上具有低电阻 和对荧光素的高（细胞旁）渗透性。这些异常都表明连接区有缺陷 屏障-治疗后和PPI治疗期间持续长达2年的屏障。此外，我们发现NSE具有低 claudin-4，紧密连接的异常，可以解释屏障功能的损害。我们有 在细胞培养物中显示，用类黄烷、槲皮素处理，导致紧密连接蛋白-4表达增加， 和改善的屏障功能。因此，我们假设NSE屏障缺陷是由低水平的 claudin-4，并且该缺陷增加了对H+的渗透性并促进了对NSE的复发性反流损伤。我们 我还假设槲皮素上调claudin-4将改善屏障功能并降低细胞内的粘附性。 NSE的脆弱性