Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis (original) (raw)

Interstitial lung disease

Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis

Tadashi Senoo1,
Noboru Hattori1,
Takuya Tanimoto1,
Makoto Furonaka1,
Nobuhisa Ishikawa1,
Kazunori Fujitaka1,
Yoshinori Haruta1,
Hiroshi Murai1,
Akihito Yokoyama2,
Nobuoki Kohno1
1Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
2Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan
Correspondence to Dr Noboru Hattori, Department of Molecular and Internal Medicine, Graduate School of Biomedical, Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; nhattori{at}hiroshima-u.ac.jp

Abstract

Background and aim There is a growing body of evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. In fact, PAI-1 knockout mice are protected from bleomycin-induced pulmonary fibrosis. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA (siRNA) targeting PAI-1 (PAI-1-siRNA) limits the development of bleomycin-induced pulmonary fibrosis.

Methods Lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) were stained for PAI-1. The distribution of siRNA in the lung, the PAI-1 level in bronchoalveolar (BAL) fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of PAI-1-siRNA in a mouse model of bleomycin-induced pulmonary fibrosis. The effect of PAI-1-siRNA on the epithelial to mesenchymal transition (EMT) was also evaluated using a mouse lung epithelial cell line, LA-4.

Results PAI-1 was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with IPF. The single intranasal instillation of PAI-1-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of PAI-1-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the PAI-1 level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor β (TGFβ) in LA-4 cells was inhibited by transfection with PAI-1-siRNA.

Conclusions The direct suppression of PAI-1 in the lung by the intrapulmonary administration of PAI-1-siRNA attenuated the development and progression of pulmonary fibrosis. The inhibition of EMT may be, at least in part, involved in this effect.

Bleomycin
epithelial to mesenchymal transition (EMT)
interstitial fibrosis
plasminogen activator inhibitors
small interfering RNA

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