大陆酸通过抑制炎症介质减轻 LPS 诱导的啮齿动物急性肺损伤，与 Nrf2 蛋白表达增加相关。

Attenuation of LPS-induced acute lung injury by continentalic acid in rodents through inhibition of inflammatory mediators correlates with increased Nrf2 protein expression.

机构信息

Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.

出版信息

BMC Pharmacol Toxicol. 2020 Nov 25;21(1):81. doi: 10.1186/s40360-020-00458-7.

DOI:10.1186/s40360-020-00458-7

PMID:33239093

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7687815/

Abstract

BACKGROUND

Acute lung injury (ALI) together with acute respiratory distress syndrome (ARDS) are associated with high rate of mortality and morbidity in patients. In the current study, the anti-inflammatory effects of continentalic acid (CNT) in LPS-induced acute lung injury model was explored.

METHODS

The acute lung injury model was established by administering LPS (5 mg/kg) intraperitonealy. Following LPS administration, the survival rate, temperature changes and lung Wet/Dry ratio were assessed. The antioxidants (GSH, GST, Catalase and SOD) and oxidative stress markers (MDA, NO, MPO) were evaluated in all the treated groups. Similarly, the cytokines such as IL-1β, IL-6 and TNF-α were analyzed using ELISA assay. The histological changes were determined using H and E staining, while Nrf2 and iNOS level were determined using immunohistochemistry analysis. The molecular docking analysis was performed to assess the pharmacokinetics parameters and interaction of the CNT with various protein targets.

RESULTS

The results showed that CNT dose dependently (10, 50 and 100 mg/kg) reduced mortality rate, body temperature and lungs Wet/Dry ratio. CNT post-treatment significantly inhibited LPS-induced production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The CNT post-treatment markedly improved the hematological parameters, while significantly reduced the MPO (indicator of the neutrophilic infiltration) activity compared to the LPS treated group. Furthermore, the CNT (100 mg/kg) post-administration remarkably inhibited the lung Wet/Dry ratio. The CNT (100 mg/kg) treated group showed marked reduction in the oxidative stress markers such as malonaldehyde (MDA) and Nitric oxide (NO) concentration, while induced the level of the anti-oxidant enzymes such as GST, GSH, Catalase and SOD. Similarly, the CNT markedly reduced the iNOS expression level, while induced the Nrf2 protein expression. Additionally, the molecular docking study showed significant binding interaction with the Nrf2, p65, Keap1, HO-1, IL-1β, IL-6, TNF-α and COX-2, while exhibited excellent physicochemical properties.

CONCLUSION

The CNT showed marked protection against the LPS-induced lung injury and improved the behavioral, biochemical and histological parameters. Furthermore, the CNT showed significant interaction with several protein targets and exhibited better physicochemical properties.

摘要

背景

急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）与患者的高死亡率和发病率有关。在本研究中，探讨了continentalic 酸（CNT）在 LPS 诱导的急性肺损伤模型中的抗炎作用。

方法

通过腹腔内给予 LPS（5mg/kg）建立急性肺损伤模型。给予 LPS 后，评估存活率、体温变化和肺湿/干比。评估所有治疗组中的抗氧化剂（GSH、GST、过氧化氢酶和 SOD）和氧化应激标志物（MDA、NO、MPO）。同样，使用 ELISA 测定法分析细胞因子，如 IL-1β、IL-6 和 TNF-α。使用 H 和 E 染色确定组织学变化，使用免疫组织化学分析确定 Nrf2 和 iNOS 水平。进行分子对接分析以评估 CNT 与各种蛋白质靶标的药代动力学参数和相互作用。

结果

结果表明，CNT 剂量依赖性地（10、50 和 100mg/kg）降低了死亡率、体温和肺湿/干比。CNT 后处理显著抑制了 LPS 诱导的促炎细胞因子如 IL-1β、IL-6 和 TNF-α的产生。CNT 后处理明显改善了血液学参数，同时与 LPS 处理组相比，显著降低了 MPO（中性粒细胞浸润的指标）活性。此外，CNT（100mg/kg）给药后明显抑制了肺湿/干比。CNT（100mg/kg）治疗组观察到氧化应激标志物如丙二醛（MDA）和一氧化氮（NO）浓度的显著降低，同时诱导了 GST、GSH、过氧化氢酶和 SOD 等抗氧化酶的水平。同样，CNT 显著降低了 iNOS 表达水平，同时诱导了 Nrf2 蛋白表达。此外，分子对接研究显示与 Nrf2、p65、Keap1、HO-1、IL-1β、IL-6、TNF-α和 COX-2 具有显著的结合相互作用，同时表现出优异的物理化学性质。