@article {Senoo334, author = {Tadashi Senoo and Noboru Hattori and Takuya Tanimoto and Makoto Furonaka and Nobuhisa Ishikawa and Kazunori Fujitaka and Yoshinori Haruta and Hiroshi Murai and Akihito Yokoyama and Nobuoki Kohno}, title = {Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis}, volume = {65}, number = {4}, pages = {334--340}, year = {2010}, doi = {10.1136/thx.2009.119974}, publisher = {BMJ Publishing Group Ltd}, 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.}, issn = {0040-6376}, URL = {https://thorax.bmj.com/content/65/4/334}, eprint = {https://thorax.bmj.com/content/65/4/334.full.pdf}, journal = {Thorax} }