Silica Nanoparticles Shed Light on Intriguing Cellular Pathways in Human Tracheal Smooth Muscle Cells: Revealing COX-2/PGE2 Production through the EGFR/Pyk2 Signaling Axis
BIOMEDICINES(2024)
摘要
The use of manufactured silica nanoparticles (SiNPs) has become widespread in everyday life, household products, and various industrial applications. While the harmful effects of crystalline silica on the lungs, known as silicosis or chronic pulmonary diseases, are well understood, the impact of SiNPs on the airway is not fully explored. This study aimed to investigate the potential effects of SiNPs on human tracheal smooth muscle cells (HTSMCs). Our findings revealed that SiNPs induced the expression of cyclooxygenase-2 (COX-2) mRNA/protein and the production of prostaglandin E-2 (PGE(2)) without causing cytotoxicity. This induction was transcription-dependent, as confirmed by cell viability assays and COX-2 luciferase reporter assays. Further analysis, including Western blot with pharmacological inhibitors and siRNA interference, showed the involvement of receptor tyrosine kinase (RTK) EGF receptor (EGFR), non-RTK Pyk2, protein kinase C alpha (PKC alpha), and p42/p44 MAPK in the induction process. Notably, EGFR activation initiated cellular signaling that led to NF-kappa B p65 phosphorylation and translocation into the cell nucleus, where it bound and stimulated COX-2 gene transcription. The resulting COX-2 protein triggered PGE(2) production and secretion into the extracellular space. Our study demonstrated that SiNPs mediate COX-2 up-regulation and PGE(2) secretion in HTSMCs through the sequential activation of the EGFR/Pyk2/PKC alpha/p42/p44MAPKs-dependent NF-kappa B signaling pathway. Since PGE(2) can have both physiological bronchodilatory and anti-inflammatory effects, as well as pathological pro-inflammatory effects, the increased PGE(2) production in the airway might act as a protective compensatory mechanism and/or a contributing factor during airway exposure to SiNPs.
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关键词
airway,cyclooxygenase-2,prostaglandin,silica oxide,nanoparticles
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