Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency
- 作者列表："Huang-Ping Yu","Fu-Chao Liu","Ani Umoro","Zih-Chan Lin","Ahmed O. Elzoghby","Tsong-Long Hwang","Jia-You Fang
Abstract Background Oleic acid (OA) is reported to show anti-inflammatory activity toward activated neutrophils. It is also an important material in nanoparticles for increased stability and cellular internalization. We aimed to evaluate the anti-inflammatory activity of injectable OA-based nanoparticles for treating lung injury. Different sizes of nanocarriers were prepared to explore the effect of nanoparticulate size on inflammation inhibition. Results The nanoparticles were fabricated with the mean diameters of 105, 153, and 225 nm. The nanocarriers were ingested by isolated human neutrophils during a 5-min period, with the smaller sizes exhibiting greater uptake. The size reduction led to the decrease of cell viability and the intracellular calcium level. The OA-loaded nanosystems dose-dependently suppressed the superoxide anion and elastase produced by the stimulated neutrophils. The inhibition level was comparable for the nanoparticles of different sizes. In the ex vivo biodistribution study, the pulmonary accumulation of nanoparticles increased following the increase of particle size. The nanocarriers were mainly excreted by the liver and bile clearance. Mice were exposed to intratracheal lipopolysaccharide (LPS) to induce acute respiratory distress syndrome (ARDS), like lung damage. The lipid-based nanocarriers mitigated myeloperoxidase (MPO) and cytokines more effectively as compared to OA solution. The larger nanoparticles displayed greater reduction on MPO, TNF-α, and IL-6 than the smaller ones. The histology confirmed the decreased pulmonary neutrophil recruitment and lung-architecture damage after intravenous administration of larger nanoparticles. Conclusions Nanoparticulate size, an essential property governing the anti-inflammatory effect and lung-injury therapy, had different effects on activated neutrophil inhibition and in vivo therapeutic efficacy.
背景: 据报道，油酸 (OA) 对活化的中性粒细胞表现出抗炎活性。它也是纳米颗粒中增加稳定性和细胞内化的重要材料。我们旨在评价可注射的基于 OA 的纳米颗粒治疗肺损伤的抗炎活性。制备不同尺寸的纳米载体，探讨纳米颗粒尺寸对炎症抑制的影响。结果制备的纳米粒平均直径为 105 、 153 和 225 nm。纳米载体在 5 min 内被分离的人中性粒细胞摄取，较小的尺寸表现出更大的摄取。尺寸的减小导致细胞活力和细胞内钙水平的降低。负载 OA 的纳米系统剂量依赖性地抑制了刺激的中性粒细胞产生的超氧阴离子和弹性蛋白酶。不同尺寸的纳米颗粒的抑制水平相当。在离体生物分布研究中，纳米颗粒的肺蓄积随着粒径的增加而增加。纳米载体主要通过肝脏和胆汁清除排泄。小鼠暴露于气管内脂多糖 (LPS) 诱导急性呼吸窘迫综合征 (ARDS)，如肺损伤。与 OA 溶液相比，基于脂质的纳米载体更有效地缓解髓过氧化物酶 (MPO) 和细胞因子。较大的纳米颗粒比较小的纳米颗粒对 MPO 、 TNF-α 和 IL-6 的还原作用更大。组织学证实静脉给予较大的纳米颗粒后肺中性粒细胞募集和肺结构损伤减少。结论纳米颗粒大小是调节抗炎作用和肺损伤治疗的重要特性，对活化中性粒细胞的抑制和体内治疗效果有不同的影响。
METHODS::Acute respiratory distress syndrome (ARDS), characterized by acute hypoxic respiratory dysfunction or failure, is a manifestation of multiple organ failure in the lung, and the most common risk factor is sepsis. We previously showed that blocking α2 -adrenoceptor (α2 -AR) could attenuate lung injury induced by endotoxin in rats. α2A -adrenoceptor (α2A -AR), a subtype of α2 -AR plays a key role in inflammatory diseases, but the mechanism remains unknown. Here, we explored the effect of BRL-44408 maleate (BRL), a specific α2A -AR antagonist, on cecal ligation puncture (CLP)-induced ARDS in rats and the underlying mechanism. Preadministration of BRL-44408 maleate significantly alleviated CLP-induced histological injury, macrophage infiltration, inflammatory response, and wet/dry ratio in lung tissue. However, there was no statistical difference in survival rate between the CLP and CLP+BRL groups. Extracellular regulated protein kinase (ERK1/2), p38MAPK, and p65 were activated in the CLP group, and BRL-44408 maleate inhibited the activation of these signal molecules, c-Jun N-terminal kinase (JNK) and protein kinase A (PKA) showed no changes in activation between these two groups. BRL-44408 maleate decreased lipopolysaccharide (LPS)-induced expression of cytokines in NR8383 rat alveolar macrophages and reduced phosphorylation of ERK1/2, p38MAPK, and p65. JNK and PKA were not influenced by LPS. Together, these findings suggest that antagonism of α2A -AR improves CLP-induced acute lung injury and involves the downregulation of ERK1/2, p38MAPK, and p65 pathway independent of the activation of JNK and PKA.