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

Exp Lung Res. 2017 Aug-Sep;43(6-7):271-282. doi: 10.1080/01902148.2017.1354946. Epub 2017 Oct 16.


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.

Keywords: Bleomycin; HSP47; pulmonary fibrosis; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / pharmacology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Collagen / metabolism*
  • Cytokines / metabolism
  • HSP47 Heat-Shock Proteins / metabolism*
  • Hydroxyproline / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Liposomes / pharmacology*
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Molecular Chaperones / metabolism*
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / metabolism
  • RNA, Small Interfering / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Vitamin A / pharmacology*


  • Cytokines
  • HSP47 Heat-Shock Proteins
  • Liposomes
  • Molecular Chaperones
  • RNA, Small Interfering
  • Serpinh1 protein, rat
  • Bleomycin
  • Vitamin A
  • Collagen
  • Hydroxyproline