Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis. Issue 4 (13th April 2010)

• Record Type: Journal Article
• Authors: Senoo, Tadashi; Hattori, Noboru; Tanimoto, Takuya; Furonaka, Makoto; Ishikawa, Nobuhisa; Fujitaka, Kazunori; Haruta, Yoshinori; Murai, Hiroshi; Yokoyama, Akihito; Kohno, Nobuoki
• Is Part Of: Thorax. Volume 65:Issue 4(2010)
• Page Start: 334
• Page End: 340
• Publication Date: 2010-04-13
• Subjects: Bleomycin -- epithelial to mesenchymal transition (EMT) -- interstitial fibrosis -- plasminogen activator inhibitors -- small interfering RNA; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thx.2009.119974
• Languages: English
• ISSNs: 0040-6376

Abstract

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.