Lung diseases are common health problems in many countries. The dysfunction of bronchial epithelial cells is important for the development of lung diseases. Recent progress reveals that inflammasome is the fundamental mechanism of epithelial activation. Here, we report the protective effect of doxofylline, a theophylline derivative agent, on lipopolysaccharides (LPS)-induced inflammatory response in bronchial epithelial cells. The presence of doxofylline reduces LPS-induced production of NO and PGE2. Doxofylline also inhibits LPS-induced production of mitochondrial ROS. Mechanistically, we show that doxofylline suppresses the expression of NOX4 induced by LPS. Doxofylline inhibits LPS-induced NLRP3-TXNIP inflammasome activation as revealed by its inhibitive effect on NLRP3, caspase 1 (P10 unit), and TXNIP induction as well as weakened induction of IL-1β and IL-18. Furthermore, we show that doxofylline ameliorates LPS-induced Sirtuin 1 (SIRT1) reduction. The silencing of SIRT1 abolishes the inhibitory effect of doxofylline on NLRP3 inflammasome activation. Collectively, our study demonstrates that doxofylline mitigates epithelial inflammation via amelioration of multiple cellular pathways, including NLRP3-TXNIP inflammasome activation.

中文翻译：

---

SIRT1在人肺支气管上皮细胞中介导了多索茶碱对脂多糖（LPS）诱导的NLRP3炎性小体活化的保护作用。

肺部疾病是许多国家/地区常见的健康问题。支气管上皮细胞功能异常对于肺部疾病的发展很重要。最近的进展表明，炎症小体是上皮激活的基本机制。在这里，我们报告茶碱衍生物阿托非茶碱对脂多糖（LPS）诱导的支气管上皮细胞炎症反应的保护作用。多索茶碱的存在降低了LPS诱导的NO和PGE2的产生。多索茶碱还抑制LPS诱导的线粒体ROS的产生。从机理上讲，我们表明多索茶碱抑制LPS诱导的NOX4的表达。多索茶碱可抑制LPS诱导的NLRP3-TXNIP炎性小体激活，如对NLRP3，半胱天冬酶1（P10单位）的抑制作用所揭示，和TXNIP诱导以及IL-1β和IL-18的诱导减弱。此外，我们显示多索茶碱可改善LPS诱导的Sirtuin 1（SIRT1）减少。SIRT1的沉默消除了多索茶碱对NLRP3炎症小体激活的抑制作用。总的来说，我们的研究表明多索茶碱通过改善多种细胞途径（包括NLRP3-TXNIP炎性体激活）减轻上皮炎症。