Abstract：
Orally marketed products nintedanib (NDNB) and pirfenidone (PFD) for pulmonary fibrosis (PF) are administered in high doses and have been shown to have serious toxic and side effects. NDNB can cause the elevation of galectin-3, which activates the NF-κB signaling pathway and causes the inflammatory response. S-allylmercapto-N-acetylcysteine (ASSNAC) can alleviate the inflammation response by inhibiting the TLR-4/NF-κB signaling pathway. Therefore, we designed and prepared inhalable ASSNAC and NDNB co-loaded liposomes for the treatment of pulmonary fibrosis. The yellow, spheroidal co-loaded liposomes with a particle size of 98.32±1.98 nm and zeta potential of -22.5 ± 1.58 mV were produced. The aerodynamic fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of NDNB were >50 % (81.14 %±0.22 %) and <5 μm (1.79 μm±0.06 μm) in the nebulized liposome solution, respectively. The results showed that inhalation improved the lung deposition and retention times of both drugs. DSPE-PEG 2000 in the liposome formulation enhanced the mucus permeability and reduced phagocytic efflux mediated by macrophages. ASSNAC reduced the mRNA over-expressions of TLR-4, MyD88 and NF-κB caused by NDNB, which could reduce the NDNB\'s side effects. The Masson\'s trichrome staining of lung tissues and the levels of CAT, TGF-β1, HYP, collagen III and mRNA expressions of Collagen I, Collagen III and α-SMA in lung tissues revealed that NDNB/Lip inhalation was more beneficial to alleviate fibrosis than oral NDNB. Although the dose of NDNB/Lip was 30 times lower than that in the oral group, the inhaled NDNB/Lip group had better or comparable anti-fibrotic effects to those in the oral group. According to the expressions of Collagen I, Collagen III and α-SMA in vivo and in vitro, the combination of ASSNAC and NDNB was more effective than the single drugs for pulmonary fibrosis. Therefore, this study provided a new scheme for the treatment of pulmonary fibrosis.
摘要：
用于肺纤维化（PF）的口服产品尼达尼布（NDNB）和吡非尼酮（PFD）以高剂量给药，并已显示具有严重的毒性和副作用。NDNB可引起半乳糖凝集素-3的升高,激活NF-κB信号通路,引起炎症反应。S-烯丙基巯基-N-乙酰半胱氨酸(ASSNAC)可通过抑制TLR-4/NF-κB信号通路缓解炎症反应。因此,我们设计并制备了可吸入ASSNAC和NDNB共负载脂质体，用于治疗肺纤维化。黄色的,产生颗粒大小为98.32±1.98nm和ζ电位为-22.5±1.58mV的球形共负载脂质体。在雾化脂质体溶液中，NDNB的空气动力学细颗粒分数（FPF）和质量中值空气动力学直径（MMAD）>50％（81.14％±0.22％）和<5μm（1.79μm±0.06μm）。分别。结果表明，吸入改善了两种药物的肺沉积和保留时间。脂质体制剂中的DSPE-PEG2000增强了粘液渗透性并减少了巨噬细胞介导的吞噬流出。ASSNAC降低了NDNB引起的TLR-4、MyD88和NF-κB的mRNA过表达，这可以减少NDNB的副作用。肺组织的Masson三色染色和CAT水平，TGF-β1,HYP,胶原蛋白III和胶原蛋白I的mRNA表达，肺组织中的胶原蛋白III和α-SMA显示，NDNB/Lip吸入比口服NDNB更有利于减轻纤维化。尽管NDNB/Lip的剂量比口服组低30倍，与口服组相比,吸入NDNB/Lip组抗纤维化效果更好或相当.根据胶原蛋白I的表达，胶原蛋白III和α-SMA的体内外，ASSNAC和NDNB联合治疗肺纤维化比单药更有效.因此,本研究为肺纤维化的治疗提供了新的方案。
