Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin 1

TLDR

ARDS is a leading cause of morbidity and mortality in critically ill patients, characterized by alveolar‑capillary barrier disruption and pulmonary edema, and currently lacks specific treatments. The study aimed to determine whether mesenchymal stem cells, with or without transfection of the vasculoprotective gene angiopoietin‑1, could ameliorate lipopolysaccharide‑induced acute lung injury in mice. Syngeneic MSCs, either unmodified or carrying a plasmid encoding human ANGPT1, were administered intravenously via the right jugular vein 30 minutes after intratracheal LPS instillation to induce lung injury. MSC treatment markedly reduced pulmonary inflammation and cytokine levels, while ANGPT1‑transfected MSCs nearly restored barrier integrity by lowering IgM and albumin leakage; MSCs were detectable in lung tissue for up to 3 days, indicating a potential therapeutic role for ANGPT1 gene‑modified MSCs in ALI/ARDS.

Abstract

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.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.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.