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首页> 外文期刊>Experimental Lung Research >Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes
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Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes

机译：用SiRNA对胶原蛋白特异性伴侣Hsp47治疗肺纤维化的治疗维生素A-偶联脂质体

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Background: Pulmonary fibrosis is a life-threatening pathological state of progressive interstitial lung diseases, such as idiopathic pulmonary fibrosis. Myofibroblasts are known to play a critical role in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the inhibitory effect of a small interfering RNA (siRNA) on a collagen-specific chaperone heat shock protein 47 (HSP47). The siRNA was preferentially delivered to myofibroblasts in a bleomycin (BLM)-induced pulmonary fibrosis rat model using siRNA against HSP47, encapsulated in a vitamin A-coupled liposome (VA-lip-siRNA HSP47). Methods and Results: Male Sprague-Dawley rats were treated with an intratracheal injection of BLM or phosphate buffered saline followed by an intravenous injection of VA-lip-siRNA HSP47 three times per week under preventive administration schedules from day 1 to day 21 and therapeutic administration schedules from day 15 to day 35. The expression of HSP47 after the treatment was assessed by immunoblotting. The specific delivery of VA-lip-siRNA HSP47 conjugated with 6'-carboxyfluoresce into myofibroblasts was examined by immunofluorescence staining. The effect of VA-lip-siRNA HSP47 on fibrosis was analyzed by morphological and biochemical methods. Preferential delivery of VA-lip-siRNA HSP47 to myofibroblasts in fibrotic areas in BLM-treated rats was verified by immunofluorescence staining. Treatment of VA-lip-siRNA HSP47 clearly suppressed HSP47 expression and induced apoptosis of myofibroblasts in the lung of BLM-treated rats. Hydroxyproline levels and inflammatory cytokines in the lungs, and the number of inflammatory cells in the bronchial alveolar lavage of BLM-treated rats were significantly suppressed by the treatment. Morphological assessment showed that VA-lip-siRNA HSP47 also significantly improved the morphological pulmonary fibrosis of BLM-treated rats in both preventive and therapeutic schedules. Conclusions: These results suggest that VA-lip-siRNA HSP47 improves pulmonary fibrosis in not only preventive, but also therapeutic schedules, and thus, this drug delivery system should provide a novel therapy for refractory pulmonary fibrosis.
机译：背景：肺纤维化是逐步间质性肺病的危及生命的病理状态，如特发性肺纤维化。已知肌纤维细胞在肺纤维化的发病机制中发挥着关键作用。该研究旨在评估小干扰RNA（siRNA）对胶​​原特异性伴侣热休克蛋白47（Hsp47）的抑制作用。优先使用siRNA在维生素A偶联脂质体（Va-Lip-siRNA Hsp47）中递送至Hsp47的肺纤维化大鼠模型中的肺纤维化大鼠模型中递送至肌纤维细胞。方法和结果：雄性Sprague-Dawley大鼠用腹腔内注射Blm或磷酸盐缓冲盐水，然后在第1天至第21天的预防施用时间表下每周静脉内注射Va-Lip-siRNA Hsp47三次，并进行治疗给药从第15天到第35天的时间表。通过免疫印迹评估治疗后HSP47的表达。通过免疫荧光染色检查将与6'-羧基荧光缀合物缀合的VA-LIP-siRNA HSP47的特定递送。通过形态学和生物化学方法分析了Va-Lip-siRNA Hsp47对纤维化的影响。通过免疫荧光染色验证了在BLM处理的大鼠中纤维化区域中的VA-LIP-siRNA HSP47的va-lip-siRNA hsp47。 VA-LIP-siRNA HSP47的处理显然抑制了HSP47的表达和诱导了BLM处理大鼠肺中肌纤维细胞的凋亡。通过治疗显着抑制了肺中肺中肺水平和炎症细胞因子，以及BLM处理的大鼠支气管肺泡灌洗中的炎性细胞的数量。形态学评估表明，VA-LIP-siRNA HSP47还显着提高了预防和治疗计划中BLM处理的大鼠的形态肺纤维化。结论：这些结果表明，VA-LIP-siRNA HSP47不仅改善了肺纤维化，不仅是预防性的，而且还可治疗计划，因此，这种药物递送系统应为难治性肺纤维化提供新的治疗。

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