Induced Pluripotent Stem Cells Alleviate Bleomycin-Induced Lung Inflammation and Fibrosis

• Main Authors: Chorng-Kuang How, 侯重光
• Other Authors: Shih-Hwa Chiou
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/17415621586634060879

博士 === 國立陽明大學 === 臨床醫學研究所 === 103 === Background: Chronic lung diseases cause serious morbidity and mortality but have no effective treatment. Induced pluripotent stem cells (iPSCs) are capable of self-renewal and differentiation into three germ layers, thereby offering potential for clinical cell-based therapies. Since the oncogene c-Myc may contribute to tumorigenesis by causing genomic instability, this study evaluated the therapeutic effect of iPSCs without exogenously introduced c-Myc on bleomycin-induced pulmonary fibrosis. Methods: Following the induction of pulmonary inflammation and fibrosis via intra-tracheal delivery of bleomycin sulphate, C57BL/6 mice were intravenously injected with 3-gene iPSCs or conditioned medium (iPSC-CM) via the tail vein at 24 hours post-bleomycin treatment. Lung injury was assessed at 3, 7, 14, and 21 days post-bleomycin through histology, pulmonary physiology, hydroxyproline assay, immuno-histochemistry, cytokines and myeloperoxidase (MPO) analysis. Results: Administration of either 3-gene iPSCs or iPSC-CM significantly attenuated collagen content and MPO activity, diminished neutrophil accumulation and rescued pulmonary function and recipient survival post-bleomycin treatment. Notably, both treatments reduced the levels of cytokines and chemokines mediating inflammation [i.e., interleukin (IL)-1, IL-2, IL-10, tumor necrosis factor (TNF)-, and monocyte chemotactic protein (MCP)-1] and fibrosis [i.e., interferon gamma (INF-) and MCP-5], yet increased the production of the anti-fibrotic chemokine INF- induced protein 10 (IP-10) in bleomycin-injured lungs. Furthermore, IP-10 neutralization via treatment with IP-10-neutralizing antibodies attenuated the reparative effect of either 3-gene iPSCs or iPSC-CM on collagen content, neutrophil and monocyte accumulation, pulmonary fibrosis and recipient survival. Conclusions: Intravenous delivery of 3-gene iPSCs/iPSC-CM alleviated the severity of histopathologic and physiologic impairment in bleomycin-induced lung fibrosis. The protective mechanism was partially mediated by the early blunting of inflammation, reduced levels of cytokines and chemokines that mediate inflammation and fibrosis, and an increased production of anti-fibrotic IP-10 in the injured lungs.