Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium
Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium
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DOI：
10.1046/j.1572-0241.2003.04018.x
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发表时间：
2004-01-01
影响因子：
9.8
通讯作者：
Orlando, RC
中科院分区：
文献类型：
--
作者：
Tobey, NA;Hosseini, SS;Orlando, RC
目的：最近已经确定，非糜烂性反流病患者在食管上皮内活检发现一种称为扩张性细胞间隙（DIS）的病变。方法：为了进一步探讨这种病变的性质和意义，我们在兔食管上皮上建立了非糜烂性酸损伤和酸-胃蛋白酶损伤的体外模型。利用这些模型进行电路分析和渗透性研究，后者使用不同大小的葡聚糖和人表皮生长因子（EGF）。结果：HCl （pH 1.1）或HCl (pH 2.0) +胃蛋白酶（1mg /ml）作用30min，可显著降低经上皮电阻（R-T），但未产生明显糜烂或细胞坏死的组织学证据。然而，透射电子显微镜证实了DIS的存在。对健康食管上皮的电路分析显示，分流电阻（R-S）远低于根尖膜、基底外膜和跨细胞电阻（R-a、R-b和R-cell），接近R-T。此外，对酸性和酸性胃蛋白酶损伤组织的电路分析表明，R-T的下降是由R-S的下降引起的。此外，R-T（以及R-S）的下降与4 kD右旋糖酐渗透率的线性增加以及6 kD EGF和20 kD右旋糖酐渗透率的增加有关。结论：在非糜烂性酸损伤的食管上皮中，DIS与上皮阻力降低和分流性增加相关，并作为其标志。在酸或酸-胃蛋白酶暴露时，这种分流性的改变是显著的，允许20 kD （33 A）大的葡聚糖分子在上皮中扩散。此外，这种分流性渗漏使6kd的管腔EGF能够扩散穿过酸损伤的上皮，从而使其能够进入上皮基底细胞上的受体。我们假设EGF的分流泄漏可能部分解释了非糜糜性反流疾病（称为基底细胞增生）患者食管活检中出现的修复现象。
OBJECTIVES: It has recently been established that patients with nonerosive reflux disease have on biopsy within esophageal epithelium a lesion known as dilated intercellular spaces (DIS).METHODS: To further explore the nature and implications of this lesion, in vitro models of nonerosive acid and acid-pepsin damage were created in Ussing chamber-mounted rabbit esophageal epithelium. Using these models circuit analysis and permeability studies were carried out, the latter using dextran of varying size and human epidermal growth factor (EGF).RESULTS: Luminal HCl, pH 1.1, or HCl, pH 2.0 + pepsin, 1 mg/ml, for 30 min significantly reduced transepithelial electrical resistance (R-T) but produced no gross erosions or histologic evidence of cell necrosis. Transmission electron microscopy, however, documented the presence of DIS. Circuit analysis on healthy esophageal epithelium showed that shunt resistance (R-S) was much lower than apical membrane, basolateral membrane and transcellular resistances (R-a, R-b, and R-cell, respectively) and approached that of R-T. Further, circuit analysis on acid and acid-pepsin damaged tissues showed that the declines in R-T resulted from declines in R-S. Moreover, the declines in R-T (and so R-S) were associated with a linear increase in permeability to 4 kD dextrans as well as an increase in permeability to 6 kD EGF and dextrans as large as 20 kD.CONCLUSIONS: In nonerosive acid-damaged esophageal epithelium DIS develop in association with and as a marker of reduced transepithelial resistance and increased shunt permeability. This change in shunt permeability upon acid or acid-pepsin exposure is substantial, permitting dextran molecules as large as 20 kD (33 A) to diffuse across the epithelium. Also, this shunt leak enables luminal EGF at 6 kD to diffuse across the acid-damaged epithelium and by so doing enables it to access its receptors on epithelial basal cells. We hypothesize that the shunt leak of EGF may in part account for the development of a reparative phenomenon on esophageal biopsy in patients with nonerosive reflux disease known as basal cell hyperplasia.