Vitex negundo Linn. extract alleviates inflammatory aggravation and lung injury by modulating AMPK/PI3K/Akt/p38-NF-κB and TGF-β/Smad/Bcl2/caspase/LC3 cascade and macrophages activation in murine model of OVA-LPS induced allergic asthma
Vitex negundo Linn. extract alleviates inflammatory aggravation and lung injury by modulating AMPK/PI3K/Akt/p38-NF-κB and TGF-β/Smad/Bcl2/caspase/LC3 cascade and macrophages activation in murine model of OVA-LPS induced allergic asthma
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DOI：
10.1016/j.jep.2021.113894
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发表时间：
2021-02-06
影响因子：
5.4
通讯作者：
Acharya, Vishal
中科院分区：
文献类型：
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作者：
Tirpude, Narendra Vijay;Sharma, Anamika;Acharya, Vishal
民族药理学相关性：越来越倾向于开发基于生物活性分子的策略来管理过敏性气道炎症相关的呼吸系统疾病。黄荆，也称为Nirgundi，是一种富含植物化学物质的药用植物，在传统医学体系中用于炎症和呼吸系统疾病，包括哮喘。初步研究表明，V. negundo Linn具有止咳和支气管扩张的潜力。本研究旨在探讨黄荆叶提取物（Vitex negundo leaf extract，VNLE）对过敏性哮喘肺损伤的影响，并探讨其作用机制。材料与方法：用卵白蛋白脂多糖（OVA-LPS）诱导Balb/c小鼠过敏性肺炎。评估了几种过敏性炎症参数、组织病理学变化、肺泡巨噬细胞活化和信号传导通路，以检查VNLE的保护作用。结果：VNLE能有效地减轻LPS诱导的巨噬细胞氧化-炎症应激，提示其具有抗炎作用。此外，VNLE在减轻哮喘肺损伤方面显示出保护作用，如通过逆转过敏原组中观察到的病理变化（包括炎性细胞流入、充血、纤维化、支气管厚度和肺泡塌陷）所证明的。VNLE抑制炎症性Th 1/Th 2细胞因子、趋化因子、内肽酶（MMPs）、氧化效应酶（iNOS）、粘附分子、IL-4/IFN-γ释放的表达，同时增强IL-10、IFN-γ、MUC 3和紧密连接蛋白的水平。随后的机制研究显示，OVA-LPS伴随着NF-κ B B、PI 3 K、Akt和p38 MAPK的磷酸化增强，并下调AMPK，这被VNLE处理明显抵消。VNLE还抑制OVA-LPS诱导的纤维化、凋亡、自噬和间隙连接蛋白，这通过TGF-β、Smad 2/3/4、Caspase 9/3、Bax、LC 3A/B、连接蛋白50、连接蛋白43的减少和Bcl 2表达的增强来证实。此外，证实了肺泡巨噬细胞活化、血液中的炎性细胞和脾CD 8 +T细胞升高的抑制。UHPLC-DAD-QTOF-ESI-IMS揭示了环烯醚萜苷和酚类化合物的存在，这可能有助于这些findings.Conclusion：这些研究结果赋予VNLE在减轻变应性肺部炎症中的保护作用，并表明它可以被认为是开发安全的天然疗法用于减轻哮喘期间的变应性炎症的有价值的药用来源。
Ethnopharmacological relevance: There is growing inclination towards developing bioactive molecule-based strategies for the management of allergic airway inflammation associated respiratory diseases. Vitex negundo Linn., also known as Nirgundi, is one such medicinal plant enriched with phytochemicals and used for inflammatory and respiratory disorders including asthma in traditional system of medicine. Preliminary studies have claimed anti-tussive and bronchodilator potential of V. negundo Linn. However, its attributes as well as molecular mechanism (s) in modulation of asthma mediated by allergic inflammation are yet to be delineated scientifically.Aim of the study: Present study attempted to assess the effectiveness of Vitex negundo leaf extract (VNLE) in mitigation of allergen induced inflammation associated asthmatic lung damage with emphasis to delineate its molecular mechanism (s).Materials and methods: Allergic lung inflammation was established in Balb/c mice using Ovalbuminlipopolysaccharide (OVA-LPS). Several allergic inflammatory parameters, histopathological changes, alveolar macrophage activation and signalling pathways were assessed to examine protective effects of VNLE. UHPLC-DAD-QTOF-ESI-IMS was used to characterize VLNE.Results: VNLE administration effectively attenuated LPS-induced oxi-inflammatory stress in macrophages suggesting its anti-inflammatory potential. Further, VNLE showed protective effect in mitigating asthmatic lung damage as evident by reversal of pathological changes including inflammatory cell influx, congestion, fibrosis, bronchial thickness and alveolar collapse observed in allergen group. VNLE suppressed expressions of inflammatory Th1/Th2 cytokines, chemokines, endopeptidases (MMPs), oxidative effector enzyme (iNOS), adhesion molecules, IL-4/IFN-gamma release with simultaneous enhancement in levels of IL-10, IFN-gamma, MUC3 and tight junction proteins. Subsequent mechanistic investigation revealed that OVA-LPS concomitantly enhanced phosphorylation of NF-kappa B, PI3K, Akt and p38MAPKs and downregulated AMPK which was categorically counteracted by VNLE treatment. VNLE also suppressed OVA-LPS induced fibrosis, apoptosis, autophagy and gap junction proteins which were affirmed by reduction in TGF-beta, Smad2/3/4, Caspase9/3, Bax, LC3A/B, connexin 50, connexin 43 and enhancement in Bcl2 expression. Additionally, suppression of alveolar macrophage activation, inflammatory cells in blood and elevation of splenic CD8+T cells was demonstrated. UHPLC-DAD-QTOF-ESI-IMS revealed presence of iridoids glycoside and phenolics which might contribute these findings.Conclusion: These findings confer protective effect of VNLE in attenuation of allergic lung inflammation and suggest that it could be considered as valuable medicinal source for developing safe natural therapeutics for mitigation of allergic inflammation during asthma.