Date Published: September 4, 2007
Publisher: Public Library of Science
Author(s): Shirley H. J Mei, Sarah D McCarter, Yupu Deng, Colleen H Parker, W. Conrad Liles, Duncan J Stewart, Mervyn Singer
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.
Partial Text: The acute respiratory distress syndrome (ARDS), a clinically important complication of severe acute lung injury (ALI) in humans, is a significant cause of morbidity and mortality in critically ill patients [1–4]. Infectious etiologies, such as sepsis and pneumonia, are leading causes of ALI/ARDS [1,2]. Histologically, ALI/ARDS in humans is characterized by a severe acute inflammatory response in the lungs and neutrophilic alveolitis . Inflammatory stimuli from microbial pathogens, such as endotoxin (lipopolysaccharide [LPS]), are well recognized for their ability to induce pulmonary inflammation, and experimental administration of LPS, both systemically and intratracheally, has been used to induce pulmonary inflammation in animal models of ALI [5–9].
In the present study, we demonstrate in a murine model of ALI that administration of MSCs to the pulmonary circulation partially prevented LPS-induced lung inflammation, whereas treatment with pANGPT1-transfected MSCs resulted in further improvement in both alveolar inflammation and permeability. These findings have potentially important implications for the treatment of ARDS, a clinical syndrome resulting from ALI, which represents an important therapeutic problem contributing to high morbidity and mortality of critically ill patients.