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      Human adult bone marrow-derived stem cells decrease severity of lipopolysaccharide-induced acute respiratory distress syndrome in sheep

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          Abstract

          Introduction

          Acute respiratory distress syndrome (ARDS) is the most common cause of respiratory failure among critically ill subjects, sepsis and severe bacterial pneumonia being its most common causes. The only interventions that have proven beneficial are protective ventilation strategies and fluid conservation approaches. New therapies are needed to address this common clinical problem. Others and we have previously shown the beneficial effect of infusion of exogenous adult stem cells in different pre-clinical models of ARDS.

          Methods

          In the present study endotoxin was infused intravenously into 14 sheep from which 6 received different doses of adult stem cells by intrabronchial delivery to evaluate the effect of stem cell therapy.

          Results

          After administration of endotoxin, there was a rapid decline in oxygenation to hypoxemic values, indicative of severe-to-moderate ARDS. None of the animals treated with saline solution recovered to normal baseline values during the 6 hours that the animals were followed. In contrast, sheep treated with a dose of 40 million adult stem cells returned their levels of oxygen in their blood to baseline two hours after the cells were infused. Similarly, improvements in carbon dioxide (CO 2) clearance, pulmonary vascular pressures and inflammation were observed and confirmed by histology and by the decrease in lung edema.

          Conclusions

          We concluded that instillation of adult non-hematopoietic stem cells can diminish the impact of endotoxin and accelerate recovery of oxygenation, CO 2 removal and inflammation in the ovine model, making the use of adult stem cells a real alternative for future therapies for ARDS.

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          Most cited references39

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          Mitochondrial transfer between cells can rescue aerobic respiration.

          Current theory indicates that mitochondria were obtained 1.5 billion years ago from an ancient prokaryote. The mitochondria provided the capacity for aerobic respiration, the creation of the eukaryotic cell, and eventually complex multicellular organisms. Recent reports have found that mitochondria play essential roles in aging and determining lifespan. A variety of heritable and acquired diseases are linked to mitochondrial dysfunction. We report here that mitochondria are more dynamic than previously considered: mitochondria or mtDNA can move between cells. The active transfer from adult stem cells and somatic cells can rescue aerobic respiration in mammalian cells with nonfunctional mitochondria.
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            Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.

            The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated. To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005. Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385). The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements. A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure. clinicaltrials.gov Identifier: NCT00188058.
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              Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.

              Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality. To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original "open-lung approach," combining low tidal volume, lung recruitment maneuvers, and high positive-end-expiratory pressure. Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia. Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250. The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475). All-cause hospital mortality. Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045). For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This "open-lung" strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies. clinicaltrials.gov Identifier: NCT00182195.
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                Author and article information

                Contributors
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central
                1757-6512
                2014
                26 March 2014
                : 5
                : 2
                : 42
                Affiliations
                [1 ]Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [2 ]Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [3 ]Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [4 ]McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [5 ]Division of Cardiothoracic Transplantation, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA
                [6 ]Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA
                Article
                scrt430
                10.1186/scrt430
                4055116
                24670268
                17b5a0d4-697e-4bec-a044-4fe75e177239
                Copyright © 2014 Rojas et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 January 2014
                : 17 February 2014
                : 21 March 2014
                Categories
                Research

                Molecular medicine
                Molecular medicine

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