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Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbalip.2019.158538 Dušan Garić 1 , Juan B De Sanctis 2 , Daciana Catalina Dumut 3 , Juhi Shah 4 , Maria Johanna Peña 5 , Mina Youssef 1 , Basil J Petrof 6 , Francisek Kopriva 7 , John W Hanrahan 8 , Marian Hajduch 7 , Danuta Radzioch 9
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbalip.2019.158538 Dušan Garić 1 , Juan B De Sanctis 2 , Daciana Catalina Dumut 3 , Juhi Shah 4 , Maria Johanna Peña 5 , Mina Youssef 1 , Basil J Petrof 6 , Francisek Kopriva 7 , John W Hanrahan 8 , Marian Hajduch 7 , Danuta Radzioch 9
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Cystic fibrosis (CF) is the most common genetic disease in Caucasians. CF is manifested by abnormal accumulation of mucus in the lungs, which serves as fertile ground for the growth of microorganisms leading to recurrent infections and ultimately, lung failure. Mucus in CF patients consists of DNA from dead neutrophils as well as mucins produced by goblet cells. MUC5AC mucin leads to pathological plugging of the airways whereas MUC5B has a protective role against bacterial infection. Therefore, decreasing the level of MUC5AC while maintaining MUC5B intact would in principle be a desirable mucoregulatory treatment outcome. Fenretinide prevented the lipopolysaccharide-induced increase of MUC5AC gene expression, without affecting the level of MUC5B, in a lung goblet cell line. Additionally, fenretinide treatment reversed the pro-inflammatory imbalance of fatty acids by increasing docosahexaenoic acid and decreasing the levels of arachidonic acid in a lung epithelial cell line and primary leukocytes derived from CF patients. Furthermore, for the first time we also demonstrate the effect of fenretinide on multiple unsaturated fatty acids, as well as differential effects on the levels of long- compared to very-long-chain saturated fatty acids which are important substrates of complex phospholipids. Finally, we demonstrate that pre-treating mice with fenretinide in a chronic model of P. aeruginosa lung infection efficiently decreases the accumulation of mucus. These findings suggest that fenretinide may offer a new approach to therapeutic modulation of pathological mucus production in CF.
中文翻译：
芬维A胺以模仿CFTR诱导的校正的方式有利地影响粘蛋白（MUC5AC / MUC5B）和脂肪酸失衡。
囊性纤维化（CF）是高加索人最常见的遗传疾病。CF以肺中粘液的异常积聚为特征，这为微生物的生长提供了肥沃的土壤，导致了反复感染并最终导致肺衰竭。CF患者的粘液由死亡中性粒细胞的DNA以及杯状细胞产生的粘蛋白组成。MUC5AC粘蛋白导致呼吸道的病理性堵塞，而MUC5B具有抵抗细菌感染的保护作用。因此，原则上降低MUC5AC的水平同时保持MUC5B完整将是理想的促凝治疗结果。芬维A胺在肺杯细胞系中阻止了脂多糖诱导的MUC5AC基因表达的增加，而没有影响MUC5B的水平。此外，芬维A胺治疗通过增加二十二碳六烯酸和降低源自CF患者的肺上皮细胞系和原代白细胞中的二十碳六烯酸并降低花生四烯酸的水平来逆转脂肪酸的促炎性失衡。此外，我们还首次证明了芬维A胺对多种不饱和脂肪酸的作用，以及与长链饱和脂肪酸相比的长链脂肪酸水平的差异作用，而长链饱和脂肪酸是复杂磷脂的重要底物。最后，我们证明在绿脓杆菌肺部感染的慢性模型中用芬维A胺预处理小鼠可有效减少粘液的积累。这些发现表明，fenretinide可能为治疗CF中病理性粘液产生的治疗提供新方法。
更新日期：2019-10-31
中文翻译：
芬维A胺以模仿CFTR诱导的校正的方式有利地影响粘蛋白（MUC5AC / MUC5B）和脂肪酸失衡。
囊性纤维化（CF）是高加索人最常见的遗传疾病。CF以肺中粘液的异常积聚为特征，这为微生物的生长提供了肥沃的土壤，导致了反复感染并最终导致肺衰竭。CF患者的粘液由死亡中性粒细胞的DNA以及杯状细胞产生的粘蛋白组成。MUC5AC粘蛋白导致呼吸道的病理性堵塞，而MUC5B具有抵抗细菌感染的保护作用。因此，原则上降低MUC5AC的水平同时保持MUC5B完整将是理想的促凝治疗结果。芬维A胺在肺杯细胞系中阻止了脂多糖诱导的MUC5AC基因表达的增加，而没有影响MUC5B的水平。此外，芬维A胺治疗通过增加二十二碳六烯酸和降低源自CF患者的肺上皮细胞系和原代白细胞中的二十碳六烯酸并降低花生四烯酸的水平来逆转脂肪酸的促炎性失衡。此外，我们还首次证明了芬维A胺对多种不饱和脂肪酸的作用，以及与长链饱和脂肪酸相比的长链脂肪酸水平的差异作用，而长链饱和脂肪酸是复杂磷脂的重要底物。最后，我们证明在绿脓杆菌肺部感染的慢性模型中用芬维A胺预处理小鼠可有效减少粘液的积累。这些发现表明，fenretinide可能为治疗CF中病理性粘液产生的治疗提供新方法。
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