Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India.
Centre of Excellence in Asthma & Lung Disease and Molecular Immunogenetics Laboratory, CSIR-Institute of Genomics and Integrative Biology, 110007, New Delhi, India.
Cell Death Dis. 2019 Jan 28;10(2):81. doi: 10.1038/s41419-018-1247-9.
Acute respiratory distress syndrome (ARDS) is characterized by an excessive acute inflammatory response in lung parenchyma, which ultimately leads to refractory hypoxemia. One of the earliest abnormalities seen in lung injury is the elevated levels of inflammatory cytokines, among them, the soluble tumor necrosis factor (TNF-α) has a key role, which exerts cytotoxicity in epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both in vitro (RAW 264.7, THP-1, MLE-12, A549, and BEAS-2B) and in vivo (C57BL/6 mice), as it activates a plethora of overlapping inflammatory signaling pathways involved in ARDS. Nimbolide is a chemical constituent of Azadirachta indica, which contains multiple biological properties, while its role in ARDS is elusive. Herein, we have investigated the protective effects of nimbolide in abrogating the complications associated with ARDS. We showed that nimbolide markedly suppressed the nitrosative-oxidative stress, inflammatory cytokines, and chemokines expression by suppressing iNOS, myeloperoxidase, and nitrotyrosine expression. Moreover, nimbolide mitigated the migration of neutrophils and mast cells whilst normalizing the LPS-induced hypothermia. Also, nimbolide modulated the expression of epigenetic regulators with multiple HDAC inhibitory activity by suppressing the nuclear translocation of NF-κB and HDAC-3. We extended our studies using molecular docking studies, which demonstrated a strong interaction between nimbolide and TNF-α. Additionally, we showed that treatment with nimbolide increased GSH, Nrf-2, SOD-1, and HO-1 protein expression; concomitantly abrogated the LPS-triggered TNF-α, p38 MAPK, mTOR, and GSK-3β protein expression. Collectively, these results indicate that TNF-α-regulated NF-κB and HDAC-3 crosstalk was ameliorated by nimbolide with promising anti-nitrosative, antioxidant, and anti-inflammatory properties in LPS-induced ARDS.
急性呼吸窘迫综合征（ARDS）的特征是肺实质中过度的急性炎症反应，最终导致难治性低氧血症。肺损伤最早出现的异常之一是炎症细胞因子水平升高，其中可溶性肿瘤坏死因子（TNF-α）起着关键作用，它对上皮细胞和内皮细胞具有细胞毒性，从而加剧水肿。细菌脂多糖（LPS）既在体外（RAW 264.7、THP-1、MLE-12、A549 和 BEAS-2B）又在体内（C57BL/6 小鼠）使用，因为它激活了大量重叠的参与 ARDS 的炎症信号通路。印苦楝内酯是印苦楝中的一种化学成分，含有多种生物学特性，但其在 ARDS 中的作用尚不清楚。在此，我们研究了印苦楝内酯在消除 ARDS 相关并发症中的保护作用。我们表明，印苦楝内酯通过抑制 iNOS、髓过氧化物酶和硝基酪氨酸的表达，显著抑制硝化-氧化应激、炎症细胞因子和趋化因子的表达。此外，印苦楝内酯减轻了中性粒细胞和肥大细胞的迁移，同时使 LPS 诱导的体温过低正常化。此外，印苦楝内酯通过抑制 NF-κB 和 HDAC-3 的核易位，调节具有多种组蛋白去乙酰化酶抑制活性的表观遗传调节剂的表达。我们使用分子对接研究扩展了我们的研究，该研究表明印苦楝内酯与 TNF-α 之间存在强烈的相互作用。此外，我们表明，用印苦楝内酯治疗可增加 GSH、Nrf-2、SOD-1 和 HO-1 蛋白表达；同时阻断 LPS 触发的 TNF-α、p38 MAPK、mTOR 和 GSK-3β 蛋白表达。总之，这些结果表明，TNF-α 调节的 NF-κB 和 HDAC-3 串扰通过印苦楝内酯得到改善，印苦楝内酯具有在 LPS 诱导的 ARDS 中具有有希望的抗硝化、抗氧化和抗炎特性。
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