含有Iloprost的新型可吸入制剂在原发性人囊性纤维化鼻上皮细胞中下调炎症细胞因子和mirna

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.550

A. Carbone , P. Soccio , E.F. Craparo , P. Vitullo , S. Bonsignore , P. Tondo , C. Scialabba , G. D'Abrosca , S. Di Gioia , D. Lacedonia , G. Cavallaro , M. Conese

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引用次数: 0

摘要

囊性纤维化（CF）肺部疾病的特征是粘液阻塞、机会性细菌感染（如铜绿假单胞菌）和无法解决的炎症反应。CF高度炎症仍然是一种罕见的药物疾病。我们的目标是开发合适的人体培养模型，以优化可吸入的智能药物传递系统，由纳米-微生物（NiM）配方组成，在模拟体内气道上皮的模型中，从而将结果转化为CF患者，以减轻肺部炎症。我们已经确定了在空气液界面（ALI）培养条件下生长的鼻上皮细胞（NEC）作为CF患者鼻刷的合适模型。方法收集8例CF个体（F508del突变纯合子或复合杂合子）的鼻上皮刷毛，采用条件重编程培养（CRC）方法扩增分离细胞。ALI培养产生内源性粘液，在不含或不含含前列环素类似物Iloprost （Ilo）的可穿透黏液的NiM制剂（聚乙二醇化或不聚乙二醇化）的情况下，用P. aeruginosa脂多糖（LPS）刺激ALI培养。real-time PCR分析与炎症相关的细胞因子（TNF-α、IL-6、IL-1ß、IL-8）和mirna （miR-145、-146a、-17）的表达。结果与LPS相比，游离Ilo和两种NiM制剂均可下调所有细胞因子。与LPS相比，NiM-PEG-Ilo显著降低了miR-145， -146a， -17的水平。结论含有Iloprost的新型可吸入NiM制剂可在先进的人类呼吸上皮细胞模型中调节CF高炎症状态，该模型是CF的体外临床前模型，由eu - nextgenerationeu项目PE_00000019资助：“创新疗法，先进实验室研究和精确医学综合方法的健康扩展联盟- heal ITALIA”。

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WS10.05Downregulation of inflammatory cytokines and miRNAs by novel inhalable formulations bearing Iloprost in primary human cystic fibrosis nasal epithelial cells

Objectives

Cystic fibrosis (CF) lung disease hallmarks are mucus obstruction, opportunistic bacterial infections (e.g. by Pseudomonas aeruginosa), and an unresolvable inflammatory response. CF hyper-inflammation remains an orphan drug condition. Our aim is to develop suitable culture models from human beings in order to optimize inhalable smart drug-delivery systems, composed by Nano-into-mycro (NiM) formulations, in models mimicking in vivo airway epithelia and so to translate results into patients with CF to dampen lung inflammation. We have identified nasal epithelial cells (NEC), grown at Air Liquid Interface (ALI) culture conditions, as a suitable model obtained from nasal brushings in CF patients.

Methods

To date, nasal epithelial brushings from 8 CF individuals (homozygous or compound heterozygous for the F508del mutation) were collected and isolated cells were expanded under conditional reprogramming culture (CRC) method. ALI cultures, producing endogenous mucus, were challenged with P. aeruginosa lipopolysaccharide (LPS) in the absence or presence of mucopenetrating NiM formulations (pegylated or not) containing Iloprost (Ilo), a prostacyclin analogue. The expression of cytokines (TNF-α, IL-6, IL-1ß, IL-8) and miRNAs (miR-145, -146a, -17), all involved in inflammation, were analyzed by real-time PCR.

Results

A downregulation for all cytokines by either free Ilo and both NiM formulations as compared with LPS only was observed. miR-145, -146a, -17 levels were significantly reduced by NiM-PEG-Ilo as compared with LPS only.

Conclusion

The CF hyper-inflammation state might be modulated by novel inhalable NiM formulations containing Iloprost in an advanced human respiratory epithelial cell model, an ex-vivo pre-clinical model for precision medicine in CF.

Funded by European Union-NextGenerationEU Project PE_00000019: “Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine-HEAL ITALIA”.

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.