Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes

被引：53

作者：

Otsuka, Mitsuo ^{[1
]}

Shiratori, Masanori ^{[1
]}

Chiba, Hirofumi ^{[1
]}

Kuronuma, Koji ^{[1
]}

Sato, Yasushi ^{[2
]}

Niitsu, Yoshiro ^{[3
]}

Takahashi, Hiroki ^{[1
]}

机构：

[1] Sapporo Med Univ, Dept Resp Med & Allergol, Sapporo, Hokkaido, Japan

[2] Sapporo Med Univ, Dept Med Oncol & Hematol, Sapporo, Hokkaido, Japan

[3] Sapporo Med Univ, Dept Mol Target Explorat, Sapporo, Hokkaido, Japan

来源：

EXPERIMENTAL LUNG RESEARCH | 2017年 / 43卷 / 6-7期

关键词：

Bleomycin; HSP47; pulmonary fibrosis; siRNA; HEPATIC STELLATE CELLS; STRESS-PROTEIN HSP47; BINDING HEAT-SHOCK-PROTEIN-47; ANTISENSE OLIGONUCLEOTIDES; INTERSTITIAL PNEUMONIA; ENDOPLASMIC-RETICULUM; INDUCED PNEUMONOPATHY; MOLECULAR CHAPERONE; LUNG; EXPRESSION;

D O I：

10.1080/01902148.2017.1354946

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

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.

引用

页码：271 / 282

页数：12

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