Abstract
BackgroundPulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis.MethodsSprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 × 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson’s trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting.ResultsSuccessful construction of a pulmonary fibrosis model was confirmed by H&E and Masson’s trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson’s trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and α-Smooth actin (α-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/β-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression.ConclusionsBMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/β-catenin signaling.ᅟᅟ
Highlights
Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present
The results demonstrate that the expression level of glycogen synthase kinase-3β (GSK-3β) was decreased in the silica model group compared with the control group, while the expression levels of P-GSK-3β, β-catenin, and Cyclin D1 were increased (p < 0.05)
We found that transplantation can reduced pathological changes to the lungs of silica-treated animals, restored epithelial characteristics, and decreased mesenchymal features as revealed by expression of specific proteins
Summary
Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. A more recent study [12] found that BMSCs can improve pulmonary fibrosis induced by silica in vivo and in vitro, but more likely through a series of paracrine factors (HGF, KGF, BMP-7), rather than by a differentiation mechanism. These studies strengthen the hypothesis that BMSC or CM may be suitable for the treatment of pulmonary fibrosis. Most of the studies have focused on the anti-inflammatory and fibrous effect of early transplantation of BMSCs or CM before silicosis occurs These findings are not really that relevant for clinical treatment, as patients present much later in the disease process than that modeled in these studies
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