Natural pachypodol integrated, lung targeted and inhaled lipid nanomedicine ameliorates acute lung injury via anti-inflammation and repairing lung barrier,Journal of Controlled Release

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Natural pachypodol integrated, lung targeted and inhaled lipid nanomedicine ameliorates acute lung injury via anti-inflammation and repairing lung barrier
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-09-17 , DOI: 10.1016/j.jconrel.2024.09.013
Zhi-Chao Sun ₁ , Ran Liao ₁ , Caihong Xian ₂ , Ran Lin ₁ , Liying Wang ₂ , Yifei Fang ₂ , Zhongde Zhang ₁ , Yuntao Liu ₁ , Jun Wu ₃

Affiliation

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic.

中文翻译：

天然 pachypodol 集成、肺靶向和吸入脂质纳米药物通过抗炎和修复肺屏障来改善急性肺损伤

急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS）是一种由 COVID-19、流感和败血症等多种疾病引起的高死亡率疾病。目前的治疗主要依赖于吸入一氧化氮或注射药物（例如糖皮质激素）;然而，它们的毒性、副作用或给药途径限制了它们的临床应用。本研究从 Pogostemon cablin Benth 中提取具有抗炎作用的疏水性黄酮醇 pachypodol （Pac），并将其嵌入脂质体（Pac@liposome，Pac-lipo）中，以提高其溶解度、生物分布和生物利用度，旨在增强 ALI/ARDS 治疗。纳米 Pac-lipo 被证实具有稳定的物理性质、良好的生物分布和可靠的生物相容性。体外试验证明，Pac-lipo 对脂多糖（LPS）诱导的巨噬细胞和内皮细胞的内皮和上皮屏障分别具有抗炎和保护作用。此外，Pac-lipo 在治疗 LPS 诱导的小鼠 ALI 中的作用得到了验证。Pac-lipo 在缓解 ALI 表型方面显示出比单独使用 Pac 更好的效果：它显着减弱肺指数，改善肺功能，抑制肺组织中 TNF-α、IL-6、IL-1β 和 iNOS 等细胞因子表达，减轻 HE 染色显示的肺损伤，降低支气管肺泡灌洗液中的蛋白质含量和总细胞数，并修复肺上皮和血管内皮屏障。关于潜在机制，RNA 测序结果表明，药物的作用与许多免疫和炎症相关的信号通路有关。分子对接和蛋白质印迹表明，Pac-lipo 抑制 TLR4-MyD88-NF-κB/MAPK 信号通路的激活。综上所述，我们的新药（Pac-lipo）首次通过抑制 TLR4-MyD88-NF-κB/MAPK 通路介导的炎症和破坏肺屏障来改善 ALI。这些发现可能为临床上的 ALI 治疗提供有前途的策略。

更新日期：2024-09-17

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