Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei City, Taiwan.
Deparment of Chemistry, Fu-Jen Catholic University, New Taipei City, Taiwan.
Pharmacol Res Perspect. 2021 Dec;9(6):e00876. doi: 10.1002/prp2.876.
Despite marked improvements in supportive care, the mortality rate of acute respiratory distress syndrome due to the excessive inflammatory response caused by direct or indirect lung injury induced by viral or bacterial infection is still high. In this study, we explored the anti-inflammatory effect of FJU-C28, a new 2-pyridone-based synthetic compound, on lipopolysaccharide (LPS)-induced inflammation in vitro and in vivo models. FJU-C28 suppressed the LPS-induced mRNA and protein expression of iNOS, COX2 and proinflammatory cytokines. The cytokine protein array results showed that LPS stimulation enhanced the secretion of IL-10, IL-6, GCSF, Eotaxin, TNFα, IL-17, IL-1β, Leptin, sTNF RII, and RANTES. Conversely, the LPS-induced secretion of RANTES, TIMP1, IL-6, and IL-10 was dramatically suppressed by FJU-C28. FJU-C28 suppressed the LPS-induced expression of RANTES, but its parental compound FJU-C4 was unable to diminish RANTES in cell culture media or cell lysates. FJU-C28 blocked the secretion of IL-6 and RANTES in LPS-activated macrophages by regulating the activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). FJU-C28 prevented the LPS-induced decreases in lung function including vital capacity (VC), lung compliance (C chord), forced expiratory volume at 100 ms (FEV100), and forced vital capacity (FVC) in mice with LPS-induced systemic inflammatory responses. FJU-C28 also reduced neutrophil infiltration in the interstitium, lung damage and circulating levels of IL-6 and RANTES in mice with systemic inflammation. In conclusion, these findings suggest that FJU-C28 possesses anti-inflammatory activities to prevent endotoxin-induced lung function decrease and lung damages by down-regulating proinflammatory cytokines including IL-6 and RANTES via suppressing the JNK, p38 MAPK and NF-κB signaling pathways.
尽管支持性治疗有了显著改善，但由于病毒或细菌感染直接或间接引起的肺损伤导致的过度炎症反应，急性呼吸窘迫综合征的死亡率仍然很高。在这项研究中，我们探讨了新型 2-吡啶酮合成化合物 FJU-C28 在体外和体内 LPS 诱导炎症模型中的抗炎作用。FJU-C28 抑制了 LPS 诱导的 iNOS、COX2 和促炎细胞因子的 mRNA 和蛋白表达。细胞因子蛋白芯片结果表明，LPS 刺激增强了 IL-10、IL-6、GCSF、Eotaxin、TNFα、IL-17、IL-1β、瘦素、sTNF RII 和 RANTES 的分泌。相反，FJU-C28 显著抑制了 LPS 诱导的 RANTES、TIMP1、IL-6 和 IL-10 的分泌。FJU-C28 抑制了 LPS 诱导的 RANTES 表达，但其母体化合物 FJU-C4 不能减少细胞培养物或细胞裂解物中的 RANTES。FJU-C28 通过调节 JNK、p38 丝裂原激活蛋白激酶 (MAPK) 和核因子-κB (NF-κB) 的激活，阻断了 LPS 激活的巨噬细胞中 IL-6 和 RANTES 的分泌。FJU-C28 防止了 LPS 诱导的全身炎症反应小鼠肺功能（包括肺活量（VC）、肺顺应性（C 弦）、100 毫秒用力呼气量（FEV100）和用力肺活量（FVC））下降。FJU-C28 还减少了全身炎症小鼠间质中的中性粒细胞浸润、肺损伤和循环 IL-6 和 RANTES 水平。总之，这些发现表明，FJU-C28 通过下调包括 IL-6 和 RANTES 在内的促炎细胞因子，通过抑制 JNK、p38 MAPK 和 NF-κB 信号通路，具有抗炎活性，可防止内毒素诱导的肺功能下降和肺损伤。
