Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae
Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae
复制标题
DOI：
10.1016/j.ejps.2009.09.001
复制
发表时间：
2009-11-05
影响因子：
4.6
通讯作者：
Brayden, David J.
中科院分区：
文献类型：
--
作者：
Maher, Sam;Kennelly, Rory;Brayden, David J.
两种吸收促进剂，（癸酸钠（C-10）和蜂毒肽），对肠道通透性和活力的影响进行了测定，在完整的大鼠和人类结肠上皮细胞安装在Ussing室。顶端侧添加C-10（10 mM）和蜂毒肽（10-50 μ M）可迅速降低跨上皮电阻（TEER），并增加[C-14]-甘露醇和FITC-葡聚糖-4 kDa（FD 4）穿过两种物种结肠粘膜的表观渗透系数（Papp）。在选定的浓度下，C-10对通量的影响大于蜂毒肽。C-10不可逆地降低TEER，但蜂毒肽的影响是部分可逆的。C-10可增强结肠粘膜中极性糖（0.18-70 kDa）的渗透性，并伴随着乳酸脱氢酶（LDH）从管腔表面的显著释放，以及抑制由毒蕈碱激动剂卡巴胆碱（0.1 - 10 μ M）诱导的产电氯化物分泌。虽然蜂毒肽不改变大鼠或人结肠粘膜的产电性氯化物分泌，但它引起大鼠组织中LDH的渗漏。大鼠和人结肠粘膜的大体组织学和电子显微镜检查表明，每种渗透增强剂在增加标记物通量所需的浓度下均可诱导结肠上皮损伤。C-10导致比蜂毒肽更显著的粘膜损伤，其特征在于脱落和粘膜糜烂。总体而言，这些结果表明，虽然C-10和蜂毒肽在体外增加了细胞旁通量标记物穿过分离的人和大鼠结肠粘膜的转运，但这些作用与一些细胞毒性相关。(C)2009 Elsevier B. V.保留所有权利。
The effects of two absorption promoters, (sodium caprate (C-10) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C-10 (10 mM) and melittin (10-50 mu M) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [C-14]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C-10 on flux were greater than those of melittin at the concentrations selected. C-10 irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18-70 kDa) in colonic mucosae with C-10 was accompanied by significant release of lactate dehydrogenase(LDH) from the luminal Surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1 - 10 mu M). Although melittin did not alter electrogenic chloride secretion in rat or human Colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C-10 led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C-10 and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity. (C) 2009 Elsevier B.V. All rights reserved.