Abstract
The present study attempts to identify the optimal time duration for the administration of Ad-MSCs, in order to maximize its therapeutic benefits, and compare the degree of fibrosis among three different administration time points using the RILF rat model system. Ad-MSCs were delivered to Sprague-Dawley rats through the tail vein at the following different time points after thorax irradiation: two hours, seven days, and two hours + seven days. Post Ad-MSCs transplantation and the histopathological analysis of the lungs were performed along with analysis of inflammatory cytokine levels, including interleukin (IL)-1, IL-2, IL-6, IL-10 and tumor necrosis factor-α (TNF-α). In particular, pro-fibrotic factors (TGF-β1 and α-SMA) were also evaluated in serum and lung tissues. In addition, it was also determined whether Ad-MSCs had any role in inhibiting the transition of type II alveolar epithelial cells into fibroblasts in the lungs of injured rats. The present results demonstrated that the intravenous delivery of Ad-MSCs twice at the 2-hour and 7-day (R + MSC2h+7d group) was effective in reducing lung fibrosis for long term durations, when compared with single delivery either at the two-hour or 7-day time points. In addition, a marked anti-inflammatory effect was also observed in RILF rats in the R + MSC2h+7d group, as indicated by the reduced serum levels of pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) and increased levels of anti-inflammatory cytokines IL-10 and IL-2. Rats that were delivered twice with Ad-MSCs (R + MSC2h+7d group) exhibited significantly reduced TGF-β1 and α-SMA levels, in contrast to rats in the R + MSC7d or R + MSC2h groups, after four weeks. Furthermore, it was also noted that after four weeks, Ad-MSCs increased the number of lung epithelial cells (SP-C) and inhibited the lung fibroblastic cells (α-SMA) of rats in the R + MSC2h and R + MSC2h+7d groups. The present study concluded that two injections of Ad-MSCs (R + MSC2h+7d group) appear to be optimal for therapeutic efficacy and safety during RILF.
Highlights
Radiation-induced lung fibrosis (RILF) represents a common and major complication due to radiotherapy, and thereby presents a threat to the health and life of patients[1,2]
Based on the clues obtained from these studies, it was proposed that the double intravenous delivery of Ad-Mesenchymal stem cells (MSCs), depending on the transforming growth factor-β1 (TGF-β1) expression, might be helpful in RILF treatment
The present study confirmed the hypothesis that the injection of adipose-derived mesenchymal stem cells (Ad-MSCs) within two hours and one week of thoracic irradiation resulted in beneficial outcomes in the treatment of RILF, when compared to one late injection after seven days (R + MSC7d group) or the radiation alone group
Summary
Radiation-induced lung fibrosis (RILF) represents a common and major complication due to radiotherapy, and thereby presents a threat to the health and life of patients[1,2]. The TGF-β1-dependent induction of myofibroblasts from lung epithelial cells has been an important step towards fibroblastic foci formation in RILF12. Multiple studies have indicated the beneficial effects of adipose-derived mesenchymal stem cells (Ad-MSCs) in injured lung tissues[16,17]. Www.nature.com/scientificreports possible mechanisms of MSC-based lung repair are not just limited to releasing autocrine or signals. Other mechanisms, such as anti-oxidation and mitochondria transfer of MSCs contribute to the lung repair[18,19]. The degree of fibrosis during three different administration times was compared using the RILF rat model system by analyzing inflammatory factors and TGF-β1 levels through its downstream effects on lung cell injury
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