Administration of pANGPT1-transfected MSCs nearly completely reversed LPS-induced increases in lung permeability, reducing IgM by 96% (CI 6%-185%) and albumin by 74% (CI 23%-126%).
Does administration of MSCs overexpressing ANGPT1 reduce pulmonary inflammation and permeability in a mouse model of LPS-induced acute lung injury?
Mesenchymal stem cells engineered to overexpress ANGPT1 significantly reduce pulmonary inflammation and restore alveolar-capillary permeability in a murine model of acute lung injury.
Effect estimate: 96% reduction in IgM, 74% reduction in albumin (95% CI 6%-185% (IgM), 23%-126% (albumin))
BACKGROUND: The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs), with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1) would have beneficial effects in experimental ALI in mice. METHODS AND FINDINGS: Syngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1) were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS) to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluid (53%, 95% confidence interval CI 7%-101%; and 60%, CI 4%-116%, respectively) as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%-185%; and 74%, CI 23%-126%, respectively). Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d. CONCLUSIONS: Treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy to treat clinical ALI/ARDS.
Mei et al. (Fri,) conducted a other in Acute lung injury (ALI). Mesenchymal stem cells (MSCs) with or without pANGPT1 transfection vs. LPS alone (implied) was evaluated on LPS-induced pulmonary inflammation and lung permeability (96% reduction in IgM, 74% reduction in albumin, 95% CI 6%-185% (IgM), 23%-126% (albumin)). Administration of pANGPT1-transfected MSCs nearly completely reversed LPS-induced increases in lung permeability, reducing IgM by 96% (CI 6%-185%) and albumin by 74% (CI 23%-126%).
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