Experimental Research For Lipopolysaccharide Induced Lung Injury With Bone Marrow-derived Mesenchymal Stem Cells Carried Agiopoietin-1

RationaleLipopolysaccharide (LPS), a major component of the cell wall of gram-negative bacteria, plays an important role in the pathogenesis of ALI/ARDS. LPS induced lung injury is characterized by microvascular protein leakage, neutrophil influx, and expression of pro inflammatory mediators, followed by severe lung damage. It is still remain little effective treatment to attenuate severe lung injury caused by LPS. Recent literature suggests that bone marrow-derived mesenchymal stem cells(MSCs) can serve as vehicle of gene therapy. We speculated that MSCs therapy combined with gene therapy might be a potential therapeutic approach for lung injury.ObjectiveTo determine whether MSCs carried with agiopoietin-1 (Ang1) could attenuate injuries of lung epithelium and endothelium in lipopolysaccharide induced lung injury.MethodsMSCs were obtained from adult male inbred mice and then were transduced with Ang1 gene efficiently through lentivirus vector. Phenotypes of MSCs were analyzed by fluorescence-activated cell sorting (FACS) before and after Ang1 transduced. Two hours after LPS inhalation, mice were infused by normal saline (NS group), lentiviral vector carried Ang1 (Ang1 group), lentiviral vector carried eGFP(MSCs group) and lentiviral vector carried Ang1/eGFP (MSCs-Ang1 group) by jugular vein injection. Ectogenic MSCs origined lung cells and Ang1 expressions in lungs were detected in receipt mice. Indexes of lung injury were evaluated at different time points. Lung myeloperoxidase activity, lung wet to dry ratio and TNF. were quantified in lung tissues of four groups.ResultsPhenotypes of MSCs were not change significantly after they were transduced with lentivirus vector. LPS-induced lung damages were attenuated and MSCs original epithelial and endothelial cells were detected in injuried lung areas 14 days after MSCs administration. Expressions of Ang1 protein in lungs were enhanced significantly 7days after MSCs-Ang1 administration. Lung MPO activities, lung W/D ratios and TNF. mRNA in lungs were attenuated 7 days after MSCs-Ang1 infusion, compared with NS group. Kaplan-Meier survival assay showed that, although did not reach statistically significance, MSCs-Ang1 infusion appeared predominance in improving survival rates of LPS-induced lung injury (p=0.066), compared with control.ConclusionsMSCs played roles of not only a vehicle but also a therapeutic cell in this study. Infusion of MSCs-Ang1 improved histopathology and Ang1 expression of injured lung, attenuated the severity of lung injury. MSCs based gene transfer of Ang1 provided a feasible, if imperfect, approach on ameliorating lung injury caused by LPS...