Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis
Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis
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DOI：
10.1136/thx.2009.119974
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发表时间：
2010-04-01
期刊：
影响因子：
10
通讯作者：
Kohno, Nobuoki
中科院分区：
文献类型：
--
作者：
Senoo, Tadashi;Hattori, Noboru;Kohno, Nobuoki
背景与目的越来越多的证据表明纤溶酶原激活物抑制剂-1 （PAI-1）参与肺纤维化的进展。事实上，PAI-1敲除小鼠可免受博莱霉素诱导的肺纤维化。本研究旨在确定肺内给予靶向PAI-1 （PAI-1-siRNA）的小干扰RNA （siRNA）是否限制博莱霉素诱导的肺纤维化的发展。方法对特发性肺纤维化（IPF）患者肺活检进行PAI-1染色。在博莱霉素诱导的肺纤维化小鼠模型中，经鼻给药PAI-1-siRNA后，评估siRNA在肺中的分布、支气管肺泡（BAL）液中PAI-1的水平以及肺纤维化改变的程度。PAI-1-siRNA对上皮细胞向间质转化（EMT）的影响也通过小鼠肺上皮细胞系LA-4进行了评估。结果PAI-1在IPF患者蜂窝状病变内壁增生性2型肺细胞中过表达。单次鼻内滴注PAI-1-siRNA导致siRNA弥漫性摄取到致密纤维化病变的上皮细胞中。在炎症期或纤维化期对博莱霉素损伤小鼠反复给予PAI-1- sirna，可降低BAL液中PAI-1的水平，并限制肺中胶原蛋白的积累。转染PAI-1-siRNA可抑制转化生长因子β (TGF β)诱导的LA-4细胞EMT。结论肺内给药PAI-1- sirna可直接抑制肺中PAI-1的表达，减轻肺纤维化的发生和进展。EMT的抑制作用可能，至少在一定程度上参与了这种作用。
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 beta (TGF beta) 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.