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

Abstract

BackgroundThe 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 FindingsSyngeneic 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.ConclusionsTreatment 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.

Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma

“…Bone marrow stromal cells (BMSCs) have recently been shown to suppress harmful immune responses in patients with acute graftversus-host disease (4,5) and in several animal models of allogeneic rejection (6)(7)(8), a variety of autoimmune diseases (9)(10)(11), and lung injury (12)(13)(14)(15). The authors of many of these studies concluded that BMSC-driven immunosuppression results from a shift in Th1/Th2 balance (8,16,17).…”

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

“…Recently, allogeneic MSC have been studied in several in vivo models of lung disease (22)(23)(24)(25). Despite initial interest in their multipotent properties (26,27), engraftment in the lung does not appear to play a major role.…”

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

“…Pathophysiologic mechanisms of ALI and ARDS include inflammation and increased endothelial and epithelial permeability to protein, resulting in extravascular accumulation of protein-rich edema fluid and alveolar epithelial injury (1). Several preclinical studies have demonstrated that bone marrow-derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of ALI induced by endotoxin (2,3), live Escherichia coli bacteria (4,5), or following sepsis (6)(7)(8). Much of the therapeutic benefit of MSCs appears to derive from the release of paracrine soluble factors, which stabilize the injured alveolar epithelium and lung endothelium, reduce inflammation, increase the absorption of pulmonary edema fluid, and have antimicrobial activity (9).…”