Adipose-Derived Mesenchymal Stem Cells Can Ameliorate Airway Remodelling and Improve Oxidative Stress: An Open Label and Randomized Clinical Trial Study on Sulfur Mustard Exposed Patients

Background: Lung is a primary target for sulfur mustard (SM) toxicity. Here, we investigated the potential efficacy and safety of adipose derived mesenchymal stem cell (AdMSC) on respiratory quality, lung regeneration, oxidative stress, and airway remodelling in patients with mustard lung. Methods: In this clinical trial study, 10 patients received 100x106 cells every 20 days for 4 injections over 8 weeks. The pulmonary function tests (PFT), chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), Borg Scale Dyspnea Assessment (BSDA), and 6 Minute Walk Test (6MWT) were evaluated. Total antioxidant capacity (TAC), malondialdehyde (MDA) and glutathione (GSH) were measured in the sputum of all samples. Changes in expression of metallothionein 3 (MT3), glutathione reductase (GR), glutathione peroxidase (GPX), and lacto peroxidase (LPO), as well as matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), transforming growth factor-b1 (TGF-b), vascular endothelial growth factor (VEGF), metallopeptidase inhibitor 1 (TIMP1), and metallopeptidase inhibitor 2 (TIMP2) were assessed using real-time PCR. Clara cell protein 16 (CC16) and Mucin-1 protein (KL-6) were measured in the sputum all samples as biomarkers of lung injury using enzyme immunoassay method. This study is registered with ClinicalTrials.gov (NCT02749448). Findings: Spirometry test results were slightly improved after each injection. A gradual improvement was observed in the mean of 6MWT scores. CASA-Q and VAS scores were increased, while means of CAT and Borg-Score were decreased. A significant improvement was found for the mean of KL-6 (p=0.022) and CC16 (p=0.005) levels. Sputum levels of TAC and GSH had a tendency to be higher after each injection, while MDA content was decreased. An improvement was observed for antioxidants genes, especially for GSR, MT3 and LPO, compared to the baseline. A gradual upregulation was found for VEGF and TGF-β expression after MSCs therapy. MSCs caused a balance between MMP9/TIMP1 and MMP2/TIMP2 ratio. The MMP2/TIMP2 ratio was decreased from 4.9 on baseline to 0.71 on day 180 (p<0.001), while the MMP9/TIMP1 ratio was declined from 16.35 on baseline to 0.64 on day 180 (p<0.001). Interpretation: The findings suggest that MSCs therapy can be safely used for improvement of lung injury and regeneration in these patients without any adverse effects. Trial Registration Number: This study is registered with ClinicalTrials.gov (NCT02749448). Funding: Iran National Science Foundation and Veterans Foundation. Declaration of Interest: The authors confirm that there are no conflicts of interest. Ethical Approval: The ethics review board of the Baqiyatallah University of Medical Sciences (Cod: IR.BMSU.REC.1393.32) approved this survey and all patients signed an informed consent letter before the study.