Lin Yan-Jyun, Yang Chien-Chung, Lee I-Ta, Wu Wen-Bin, Lin Chih-Chung, Hsiao Li-Der, Yang Chuen-Mao
Institute of Translational Medicine and New Drug Development, College of Medicine, China Medical University, Taichung 40402, Taiwan.
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan 33302, Taiwan.
Biomedicines. 2023 Sep 25;11(10):2628. doi: 10.3390/biomedicines11102628.
The risk of lung exposure to silica nanoparticles (SiNPs) and related lung inflammatory injury is increasing with the wide application of SiNPs in a variety of industries. A growing body of research has revealed that cyclooxygenase (COX)-2/prostaglandin E (PGE) up-regulated by SiNP toxicity has a role during pulmonary inflammation. The detailed mechanisms underlying SiNP-induced COX-2 expression and PGE synthesis remain unknown. The present study aims to dissect the molecular components involved in COX-2/PGE up-regulated by SiNPs in human pulmonary alveolar epithelial cells (HPAEpiCs) which are one of the major targets while SiNPs are inhaled. In the present study, we demonstrated that SiNPs induced COX-2 expression and PGE release, which were inhibited by pretreatment with a reactive oxygen species (ROS) scavenger (edaravone) or the inhibitors of proline-rich tyrosine kinase 2 (Pyk2, PF-431396), epidermal growth factor receptor (EGFR, AG1478), phosphatidylinositol 3-kinase (PI3K, LY294002), protein kinase B (Akt, Akt inhibitor VIII), p38 mitogen-activated protein kinase (MAPK) (p38 MAPK inhibitor VIII), c-Jun N-terminal kinases (JNK)1/2 (SP600125), Forkhead Box O1 (FoxO1, AS1842856), and activator protein 1 (AP-1, Tanshinone IIA). In addition, we also found that SiNPs induced ROS-dependent Pyk2, EGFR, Akt, p38 MAPK, and JNK1/2 activation in these cells. These signaling pathways induced by SiNPs could further cause c-Jun and FoxO1 activation and translocation from the cytosol to the nucleus. AP-1 and FoxO1 activation could increase COX-2 and PGE levels induced by SiNPs. Finally, the COX-2/PGE axis might promote the inflammatory responses in HPAEpiCs. In conclusion, we suggested that SiNPs induced COX-2 expression accompanied by PGE synthesis mediated via ROS/Pyk2/EGFR/PI3K/Akt/p38 MAPK- and JNK1/2-dependent FoxO1 and AP-1 activation in HPAEpiCs.
随着二氧化硅纳米颗粒（SiNPs）在各种行业中的广泛应用，肺部暴露于SiNPs及相关肺部炎性损伤的风险正在增加。越来越多的研究表明，由SiNP毒性上调的环氧化酶（COX）-2/前列腺素E（PGE）在肺部炎症过程中发挥作用。SiNP诱导COX-2表达和PGE合成的详细机制仍不清楚。本研究旨在剖析在人肺泡上皮细胞（HPAEpiCs）中，由SiNPs上调的COX-2/PGE所涉及的分子成分，而HPAEpiCs是吸入SiNPs时的主要靶细胞之一。在本研究中，我们证明SiNPs诱导COX-2表达和PGE释放，而用活性氧（ROS）清除剂（依达拉奉）或富含脯氨酸的酪氨酸激酶2（Pyk2，PF-431396）、表皮生长因子受体（EGFR，AG1478）、磷脂酰肌醇3-激酶（PI3K，LY294002）、蛋白激酶B（Akt，Akt抑制剂VIII）、p38丝裂原活化蛋白激酶（MAPK）（p38 MAPK抑制剂VIII）、c-Jun氨基末端激酶（JNK）1/2（SP600125）、叉头框O1（FoxO1，AS1842856）和活化蛋白1（AP-1，丹参酮IIA）进行预处理可抑制上述反应。此外，我们还发现SiNPs在这些细胞中诱导ROS依赖性的Pyk2、EGFR、Akt、p38 MAPK和JNK1/2激活。这些由SiNPs诱导的信号通路可进一步导致c-Jun和FoxO1激活并从细胞质转位至细胞核。AP-1和FoxO1激活可增加SiNPs诱导的COX-2和PGE水平。最后，COX-2/PGE轴可能促进HPAEpiCs中的炎症反应。总之，我们认为SiNPs在HPAEpiCs中诱导COX-2表达并伴有通过ROS/Pyk2/EGFR/PI3K/Akt/p38 MAPK和JNK1/2依赖性的FoxO1和AP-1激活介导的PGE合成。
