Matrix metalloproteinase-7 induces E-cadherin cleavage in acid-exposed primary human pharyngeal epithelial cells via the ROS/ERK/c-Jun pathway.
Matrix metalloproteinase-7 induces E-cadherin cleavage in acid-exposed primary human pharyngeal epithelial cells via the ROS/ERK/c-Jun pathway.
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DOI：
10.1007/s00109-021-02166-z
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Baek SK
中科院分区：
文献类型：
--
作者：
Im NR;Kim B;Jung KY;Baek SK
喉咽反流病（LPRD）是由于胃内容物（包括胃酸、胃蛋白酶和胆汁）反流而导致咽黏膜损伤而引起的。我们之前的研究表明，LPRD与e-钙粘蛋白的裂解有关，这是由酸激活的基质金属蛋白酶-7 （MMP-7）促进的；然而，酸激活MMP-7的机制尚不清楚。本研究的目的是探讨MMP-7在暴露于酸的咽上皮细胞中被激活的机制。在暴露于酸的上皮细胞中测量活性氧（ROS）的水平。为了探讨ROS在MMP-7表达中的信号机制，我们考察了丝裂原活化蛋白激酶的作用机制。根据酸暴露的咽上皮细胞中每种抑制剂的存在或不存在来确定各种信号因子的表达。为了确定e -钙粘蛋白裂解的变化，使用经上皮通透性试验评估粘膜的完整性。我们发现，酸暴露增加了咽部上皮细胞中ROS、磷酸化细胞外信号调节激酶（p-ERK） 1/2和磷酸化c- jun （p-c-Jun）的水平。ROS抑制剂降低了p-ERK和MMP-7的表达，ERK抑制剂降低了p-c-Jun和MMP-7的表达。此外，c-Jun抑制剂可降低MMP-7的表达，阻断E-cadherin的降解。此外，ROS、ERK和c-Jun抑制剂共同缓解了酸暴露后免疫染色E-cadherin水平的降低和经皮通透性的增加。人粘膜细胞暴露于酸后发生的E-cadherin降解似乎是由MMP-7通过ROS/ERK/c-Jun通路表达增加引起的，这被认为是与LPRD发展相关的重要机制。•当反流发生时触发ROS。•ROS通过ERK途径调控转录因子c-Jun。•诱导LPRD的MMP-7的增加是通过ROS/ERK/c-Jun途径诱导的。•本研究首次揭示了LPRD病因之一MMP-7的表达机制。在线版本包含补充材料，可在10.1007/s00109-021-02166-z获得。
Laryngopharyngeal reflux disease (LPRD) is caused by pharyngeal mucosal damage due to the reflux of gastric contents, including acid, pepsin, and bile juice. Our previous study has demonstrated that LPRD is associated with the cleavage of E-cadherin, which is facilitated by the acid-activated matrix metalloproteinase-7 (MMP-7); however, the mechanism by which the acid activates MMP-7 remains unclear. The purpose of this study was to investigate the mechanism by which MMP-7 is activated in the pharyngeal epithelial cells that are exposed to acid. The levels of reactive oxygen species (ROS) were measured in the epithelial cells exposed to acid. To investigate the signaling mechanism of ROS in the expression of MMP-7, the mechanism of action of the mitogen-activated protein kinase was examined. The expression of various signaling factors was determined, according to the presence or absence of each inhibitor in the acid-exposed pharyngeal epithelial cells. To identify changes in the cleavage of E-cadherin, the integrity of the mucosal membrane was assessed using a transepithelial permeability test. We found that acid exposure increased the levels of ROS, phosphorylated-extracellular signal-regulated kinase (p-ERK) 1/2, and phosphorylated-c-Jun (p–c-Jun) in pharyngeal epithelial cells. The ROS inhibitor reduced the expression of p-ERK and MMP-7, while the ERK inhibitor reduced the expression of p–c-Jun and MMP-7. Moreover, the c-Jun inhibitor reduced the expression of MMP-7 and blocked the degradation of E-cadherin. In addition, decrease in the levels of immunostained E-cadherin and increase in transepithelial permeability after acid exposure were collectively alleviated by the inhibitors of ROS, ERK, and c-Jun. The degradation of E-cadherin that occurs after human mucosal cells are exposed to acid appears to be caused by an increase in the expression of MMP-7 via the ROS/ERK/c-Jun pathway, which is thought to be an important mechanism associated with the development of LPRD. • ROS is triggered when reflux occurs. • ROS regulates the transcription factor c-Jun via the ERK pathway. • The increase in MMP-7 that induces LPRD is induced via the ROS/ERK/c-Jun pathway. • This study revealed for the first time the expression mechanism of MMP-7, which is one of the causes of LPRD. The online version contains supplementary material available at 10.1007/s00109-021-02166-z.
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