Abstract
Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS) cells have been considered as an ideal resource for stem cell-based therapy. Although, an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF)-β1 signaling pathway, and epithelial to mesenchymal transition (EMT) during bleomycin (BLM)-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg) was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free) were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2) to its tissue inhibitor -2 (TIMP-2) and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3) and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM) profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse alveolar epithelial type II cells (AECII). Collectively, our results suggest that transplantation of iPS cells could suppress inflammatory responses, TGF-β1/Smad2/3 pathway and EMT during the progression of BLM-induced pulmonary fibrosis, providing new useful clues regarding the mechanisms of iPS cells in the treatment for this disease.
Highlights
Pulmonary fibrosis is a chronic interstitial lung disease, which is characterized by inflammatory injury of alveolar epithelial cells, excessive proliferation of fibroblasts, aberrant deposition of extracellular matrix (EMC), and abnormal repair and remodeling of lung tissue (White et al, 2003)
We developed a BLM-induced pulmonary fibrosis mouse model, and demonstrated that amelioration of pulmonary inflammation and inhibition of transforming growth factor (TGF)-β1 signaling and epithelial to mesenchymal transition (EMT) process were involved in the anti-fibrotic effects of induced pluripotent stem (iPS) cells
Our findings suggest that the inhibitory effects of iPS cells on pulmonary fibrosis may partly attribute to the suppression of TGF-β1-Smad2/3-EMT pathway
Summary
Pulmonary fibrosis is a chronic interstitial lung disease, which is characterized by inflammatory injury of alveolar epithelial cells, excessive proliferation of fibroblasts, aberrant deposition of extracellular matrix (EMC), and abnormal repair and remodeling of lung tissue (White et al, 2003). These pathologic changes result in progressive decline in pulmonary function, eventually leading to respiratory failure (Wynn, 2011). In the past few years, TGF-β1 pathway has attracted considerable attention from researchers as a therapeutic target for lung fibrosis (D’Alessandro-Gabazza et al, 2012; Dong et al, 2012). Exploring new effective strategies for ameliorating pulmonary fibrosis is a top priority
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