Abstract
242267
Introduction: [18F]FDG is commonly used for the diagnosis of various cancers, inflammatory conditions, and myocardial infarction. In this study, [18F]FDG is employed to assess the extent of intimal inflammation in outflow vein during the process of neointimal hyperplasia (NIH) after arteriovenous fistula (AVF) creation. Typically, [18F]FDG shows accelerated uptake into tumor cells, hypoxic and inflammatory cells with enhanced anaerobic glucose metabolism. These cells show highly expressed glucose transporters and an increase in anaerobic glycolysis compared to healthy cells. Since the NIH is perceived to be result of combination of inflammation, hypoxia, oxidative stress, and smooth muscle hyperplasia, the cells in the outflow vein of AVF should show higher uptake of [18F]FDG. The current study aims to evaluate and compare the therapeutic efficacy of antiinflammatory, antiproliferative mesenchymal stem cells and the senolytic drugs Dasatinib (kinase inhibitor) and Quercetin (Antioxidant, Proapoptotic) as monotherapy and combined therapy, in normal C57BL/6 mice (control) and C57BL/6 mice with AV fistula using [18F]FDG PETfor up to 28 days post AVF surgery.
Methods: Healthy C57BL/6 mice were selected to create AV Fistula between right external jugular vein and left common carotid artery, producing an end to side anastomosis. The mice with AVF were randomized into three groups based on the treatments as (i) Vehicle (normal saline / PBS, n = 4), (ii) MSC (n = 4), (iii) MSC, Dasatinib and Quercetin (n = 4). A separate control group (n = 4) without AVF or any treatments mentioned before were also included. Adventitia of the sequent outflow vein is treated with stabilized mesenchymal stem cells sourced from human adipose tissue immediately after anastomosis in the MSC and MSC+Drug treated group. All animals were injected with 5-10 microliter of 1.48-1.85 MBq of [18F]FDG through tail vein under 2-3 % isoflurane anesthesia. Static PET imaging (10 min) was performed at 2 h, day-2, week-1, week-2, week-4 post surgery at 30 and 60 min post injection of [18F]FDG . Obtained images were analyzed to calculate the standard uptake value (SUV) by drawing regions of interest including AVF, brain, liver, and kidney through Amide software. Relative uptake of [18F]FDG in all the groups have been analyzed and multifold comparisons were made using student T test.
Results: The outflow vein of MSC treated group showed lower SUVmean of 1.32±0.41 at 30 min, (n=4) and 1.23±0.36 at 60 min, (n=4) as compared to the vehicle treated control group with AVF showing SUVMean of 2.03±0.18 (n=4) and 1.71±0.21 (n=4) at 30 min and 60 min, respectively postinjection of [18F]FDG on day-2 post treatment. Also, a significant decrease in uptake of the [18F]FDG was observed in MSC and Dasatinib+Quercetin treated group on day 7 (SUVMean 1.76±0.07 at 60 min, post [18F]FDG injection, n=3) and on day 28 (SUVMean 1.39±0.03 at 30 min post [18F]FDG injection, n = 3) compared to the vehicle treated control group on day 7 (SUVMean 2.38±0.47 at 60 min post [18F]FDG injection, n = 4) and on day 28 (SUVMean 1.56±0.09 at 30 min post [18F]FDG injection, n = 4). No significant difference in [18F]FDG uptake was observed at day 14 between either the MSC and control or MSC with drug treated and control groups. Apart from AVF site, higher uptake was also observed in heart followed by brain, kidney and liver as presented in the figure 1.
Conclusions: Implantation of MSCs, dasatinib (kinase inhibitor) and quercetin (Antioxidant) into adventitia showed a reduction in the uptake of [18F]FDG on day 28 as compared to vehicle treated control group at 30 min post [18F]FDG administration. Lower uptake of [18F]FDG implies the potential anti-inflammation effect of MSC and D&Q, which might be effective in inhibiting neointimal hyperplasia in outflow vein after AVF creation. Acknowledgement: This study is funded by the National Heart, Lung and Blood Institute, USA (RO1, HL98967 PI- Misra).
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