Newly Published
Critical Care Medicine  |   July 2018
Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats
Author Notes
  • From the Regenerative Medicine Institute at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland (C.M., J.D., S.H., F.B., T.O., D.O., J.G.L.); Orbsen Therapeutics Ltd., Galway, Ireland (L.O., L.D., S.E.); School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland (F.B., T.O., D.O., J.G.L.); Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospitals, SAOLTA University Health Group, Galway, Ireland (T.O.); Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, Galway, Ireland (J.G.L.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • C.M. and J.D. contributed equally to the work.
    C.M. and J.D. contributed equally to the work.×
  • Submitted for publication September 12, 2017. Accepted for publication May 24, 2018.
    Submitted for publication September 12, 2017. Accepted for publication May 24, 2018.×
  • Deceased.
    Deceased.×
  • Research Support: Supported by funding from the European Research Council (Brussels, Belgium) under the Framework 7 Programme (ERC-2007-StG 207777, to Dr. Laffey), Science Foundation Ireland (16/FRL/3845, to Dr. Laffey), the Health Research Board Ireland (HRA-POR-2015-1099, to Dr. O’Toole), and from Orbsen Therapeutics Ltd. (Galway, Ireland). The cells used in these studies were provided free of charge by Orbsen Therapeutics Ltd.
    Research Support: Supported by funding from the European Research Council (Brussels, Belgium) under the Framework 7 Programme (ERC-2007-StG 207777, to Dr. Laffey), Science Foundation Ireland (16/FRL/3845, to Dr. Laffey), the Health Research Board Ireland (HRA-POR-2015-1099, to Dr. O’Toole), and from Orbsen Therapeutics Ltd. (Galway, Ireland). The cells used in these studies were provided free of charge by Orbsen Therapeutics Ltd.×
  • Competing Interests: Dr. Elliman is the Chief Scientific Officer, Dr. O’Flynn is the Head of Process Development, and Dr. Deedigan is Head of Analytical Development, at Orbsen Therapeutics Ltd. (Galway, Ireland), a company that is developing the CD362+ mesenchymal stromal cells for therapeutic purposes. Prof. O’Brien and Prof. Barry are directors of and equity holders in Orbsen Therapeutics. The other authors declare no competing interests.
    Competing Interests: Dr. Elliman is the Chief Scientific Officer, Dr. O’Flynn is the Head of Process Development, and Dr. Deedigan is Head of Analytical Development, at Orbsen Therapeutics Ltd. (Galway, Ireland), a company that is developing the CD362+ mesenchymal stromal cells for therapeutic purposes. Prof. O’Brien and Prof. Barry are directors of and equity holders in Orbsen Therapeutics. The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Laffey: Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland. john.laffey@nuigalway.ie. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Respiratory System
Critical Care Medicine   |   July 2018
Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats
Anesthesiology Newly Published on July 3, 2018. doi:10.1097/ALN.0000000000002327
Anesthesiology Newly Published on July 3, 2018. doi:10.1097/ALN.0000000000002327
Abstract

What We Already Know about This Topic:

  • Human mesenchymal stromal cells diminish injury and enhance recovery and repair after ventilator-induced lung injury in animals

  • Current methods of isolating mesenchymal stromal cells result in a heterogeneous mix of cell types, which may be suboptimal

What This Article Tells Us That Is New:

  • Pure subpopulations of bone marrow–derived human mesenchymal stromal cells were isolated on the basis of expression of the cell surface marker syndecan 2

  • Intravenous injection of these cells attenuated Escherichia coli–induced injury and enhanced resolution of ventilator-induced lung injury in rats, reducing lung inflammation and histologic injury and improving lung compliance and arterial oxygenation

  • Cells expressing syndecan 2 were more effective than those not expressing syndecan 2

Background: Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)–expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli–induced lung injury and enhance resolution after ventilator-induced lung injury.

Methods: In vitro studies determined whether CD362+ human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group).

Results: CD362+ human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced injury in rodents, improving arterial oxygenation (mean ± SD, 83 ± 9 vs. 60 ± 8 mmHg, P < 0.05), improving lung compliance (mean ± SD: 0.66 ± 0.08 vs. 0.53 ± 0.09 ml · cm H2O−1, P < 0.05), reducing bacterial load (median [interquartile range], 1,895 [100–3,300] vs. 8,195 [4,260–8,690] colony-forming units, P < 0.05), and decreasing structural injury compared with vehicle. CD362+ human mesenchymal stromal cells were more effective than CD362 human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362+ human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean ± SD: 113 ± 11 vs. 89 ± 11 mmHg, P < 0.05) and lung static compliance (mean ± SD: 0.74 ± 0.07 vs. 0.45 ± 0.07 ml · cm H2O−1, P < 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362+ human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells.

Conclusions: A CD362+ human mesenchymal stromal cell population decreased Escherichia coli–induced pneumonia severity and enhanced recovery after ventilator-induced lung injury.