Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, 3054 Life Sciences Building, Provo, UT, 84602, USA.
Environ Sci Pollut Res Int. 2018 Jun;25(18):18179-18188. doi: 10.1007/s11356-018-1985-3. Epub 2018 Apr 25.
Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-α and IL-1β were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution.
Claudin-6 (Cldn6) 是一种四跨膜蛋白，有助于紧密连接复合体的形成，并与肺上皮屏障的维持有关。在本研究中，我们检验了这样一个假设，即 Cldn-6 的基因上调会影响短期暴露于环境柴油颗粒物 (DPM) 的小鼠的炎症反应。通过鼻腔吸入系统（Scireq，蒙特利尔，加拿大），将小鼠暴露于雾化的 DPM（PM2.5）中，共进行了 10 次，持续 20 天。使用实时 RT-PCR，我们发现 Cldn6 基因在 DPM 暴露的对照组小鼠和上调 Cldn-6 的肺特异性转基因小鼠中均上调。有趣的是，DPM 并未进一步增强 Cldn-6 TG 小鼠中的 Cldn-6 表达。DPM 导致对照组小鼠的细胞渗出到支气管肺泡灌洗液（BALF）中增加；然而，Cldn-6 TG 小鼠在 DPM 暴露后 BALF 中的总细胞数和 PMN 较少。由于 Cldn-6 TG 小鼠的细胞渗出减少，因此筛选了其他炎症介质来表征增加 Cldn-6 对炎症信号的影响。在 DPM 暴露后，介导炎症反应的细胞因子，包括 TNF-α和 IL-1β，在 Cldn6 TG 小鼠和对照组中呈现不同的调节。这些结果表明，由 Cldn-6 组织的上皮屏障至少部分介导了柴油引起的炎症。进一步的研究可能表明，Cldn-6 是理解环境污染加剧的肺上皮门户的关键靶点。
