Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan 30013, ROC.
Biomaterials. 2012 Sep;33(26):6254-63. doi: 10.1016/j.biomaterials.2012.05.013. Epub 2012 Jun 7.
Chitosan (CS) and its derivatives have been investigated as paracellular permeation enhancers for facilitating the oral bioavailability of hydrophilic macromolecules. As is well known, CS can transiently open the tight junctions (TJs) between epithelial cells, thus enhancing the paracellular permeability. However, the signaling mechanism that is related to the effect of CS on TJs remains unclear. Therefore, this study elucidates the potential transduction cascade of TJ opening in Caco-2 cell monolayers subsequent to CS exposure. Experimental results indicate that activation of integrin receptors on cell membranes significantly contributes to CS-mediated TJ disruption, initiating the cascade of TJ opening. Additionally, treatment of Caco-2 cell monolayers with CS leads to the clustering of integrins along the cell border, phosphorylation of FAK and Src tyrosine kinases, and results in the regulation of TJ permeability via the redistribution of TJ protein CLDN4 from the cell membrane to the cytosol. Elucidating the signaling mechanism of CS-induced TJ opening in intestinal cells significantly contributes to efforts to use CS and its derivatives as paracellular permeation enhancers.
壳聚糖（CS）及其衍生物已被研究为细胞旁渗透增强剂，以促进亲水分子的口服生物利用度。众所周知，CS 可以瞬时打开上皮细胞之间的紧密连接（TJ），从而增强细胞旁通透性。然而，与 CS 对 TJ 的作用相关的信号机制尚不清楚。因此，本研究阐明了 CS 暴露后 Caco-2 细胞单层中 TJ 开放的潜在转导级联。实验结果表明，细胞膜上整合素受体的激活对 CS 介导的 TJ 破坏有重要贡献，启动了 TJ 开放的级联反应。此外，CS 处理 Caco-2 细胞单层会导致整合素沿着细胞边界聚集，粘着斑激酶（FAK）和Src 酪氨酸激酶磷酸化，并通过将 TJ 蛋白 CLDN4 从细胞膜重新分布到细胞质来调节 TJ 通透性。阐明 CS 诱导的肠道细胞 TJ 开放的信号机制，有助于将 CS 及其衍生物用作细胞旁渗透增强剂。
