School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China; Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
Phytomedicine. 2022 Dec;107:154380. doi: 10.1016/j.phymed.2022.154380. Epub 2022 Aug 3.
Acute lung injury (ALI) is a severe respiratory disease characterized by diffuse lung interstitial and respiratory distress and pulmonary edema with a mortality rate of 35%-40%. Inula japonica Thunb., known as "Xuan Fu Hua" in Chinese, is a traditional Chinese medicine Inulae Flos to use for relieving cough, eliminating expectorant, and preventing bacterial infections in the clinic, and possesses an anti-pulmonary fibrosis effect. However, the effect and action mechanism of I. japonica on ALI is still unclear.
This study aimed to investigate the protective effect and underlying mechanism of total flavonoids of I. japonica (TFIJ) in the treatment of ALI.
A mouse ALI model was established through administration of LPS by the intratracheal instillation. Protective effects of TFIJ in the inflammation and oxidative stress were studied in LPS-induced ALI mice based on inflammatory and oxidative stress factors, including MDA, MPO, SOD, and TNF-α. Lipid metabolomics, bioinformatics, Western blot, quantitative real-time PCR, and immunohistochemistry were performed to reveal the potential mechanism of TFIJ in the treatment of ALI.
TFIJ significantly alleviated the interstitial infiltration of inflammatory cells and the collapse of the alveoli in LPS-induced ALI mice. Lipid metabolomics demonstrated that TFIJ could significantly affect the CYP2J/sEH-mediated arachidonic acid metabolism, such as 11,12-EET, 14,15-EET, 8,9-DHET, 11,12-DHET, and 14,15-DHET, revealing that sEH was the potential target of TFIJ, which was further supported by the recombinant sEH-mediated the substrate hydrolysis in vitro (IC = 1.18 μg/ml). Inhibition of sEH by TFIJ alleviated the inflammatory response and oxidative stress via the MAPK, NF-κB, and Nrf2 signaling pathways.
These results demonstrated that TFIJ could suppress the sEH activity to stabilize the level of EETs, allowing the alleviation of the pathological course of lung injury in LPS-treated mice, which suggested that TFIJ could serve as the potential agents in the treatment of ALI.
急性肺损伤（ALI）是一种严重的呼吸系统疾病，其特征为弥漫性肺间质和呼吸窘迫以及肺水肿，死亡率为 35%-40%。旋覆花，在中国被称为“旋覆花”，是一种传统的中药，用于临床止咳、化痰、预防细菌感染，具有抗肺纤维化作用。然而，旋覆花对 ALI 的作用和作用机制仍不清楚。
本研究旨在探讨旋覆花总黄酮（TFIJ）治疗 ALI 的保护作用及其潜在机制。
通过气管内滴注 LPS 建立小鼠 ALI 模型。基于炎症和氧化应激因子，包括 MDA、MPO、SOD 和 TNF-α，研究 TFIJ 对 LPS 诱导的 ALI 小鼠的炎症和氧化应激的保护作用。采用脂质组学、生物信息学、Western blot、实时定量 PCR 和免疫组织化学等方法揭示 TFIJ 治疗 ALI 的潜在机制。
TFIJ 显著减轻了 LPS 诱导的 ALI 小鼠的炎症细胞间质浸润和肺泡塌陷。脂质组学表明，TFIJ 可显著影响 CYP2J/sEH 介导的花生四烯酸代谢，如 11,12-EET、14,15-EET、8,9-DHET、11,12-DHET 和 14,15-DHET，表明 sEH 是 TFIJ 的潜在靶点，这进一步得到了重组 sEH 体外介导的底物水解的支持（IC=1.18μg/ml）。TFIJ 通过 MAPK、NF-κB 和 Nrf2 信号通路抑制 sEH，从而减轻炎症反应和氧化应激。
这些结果表明，TFIJ 可以抑制 sEH 的活性，稳定 EETs 的水平，从而缓解 LPS 处理的小鼠肺损伤的病理过程，这表明 TFIJ 可作为治疗 ALI 的潜在药物。
