Jonathan E Millar1,2,3, Nicole Bartnikowski1,4, Margaret R Passmore1,2, Nchafatso G Obonyo1,5, Maximillian V Malfertheiner1,6, Viktor von Bahr1,7, Meredith A Redd8, Louise See Hoe1,2, Katrina K Ki1,2, Sanne Pedersen1,4, Andrew J Boyle3, J Kenneth Baillie9, Kiran Shekar1,2, Nathan Palpant8, Jacky Y Suen1,2, Michael A Matthay10,11, Daniel F McAuley3, John F Fraser1,2. 1. Critical Care Research Group, the Prince Charles Hospital, Brisbane, Queensland, Australia. 2. Faculty of Medicine and. 3. Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom. 4. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. 5. Wellcome Trust Centre for Global Health Research, Imperial College London, London, United Kingdom. 6. Department of Internal Medicine II, Cardiology and Pneumology, University Medical Center Regensburg, Regensburg, Germany. 7. Section for Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 8. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. 9. Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom; and. 10. Department of Medicine and. 11. Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
Abstract
Rationale: Mesenchymal stromal cell (MSC) therapy is a promising intervention for acute respiratory distress syndrome (ARDS), although trials to date have not investigated its use alongside extracorporeal membrane oxygenation (ECMO). Recent preclinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO. Objectives: To determine the safety and efficacy of MSC therapy in a model of ARDS and ECMO. Methods: ARDS was induced in 14 sheep, after which they were established on venovenous ECMO. Subsequently, they received either endobronchial induced pluripotent stem cell-derived human MSCs (hMSCs) (n = 7) or cell-free carrier vehicle (vehicle control; n = 7). During ECMO, a low Vt ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analyzed, in addition to continuous respiratory and hemodynamic monitoring.Measurements and Main Results: The administration of hMSCs did not improve oxygenation (PaO2/FiO2 mean difference = -146 mm Hg; P = 0.076) or pulmonary function. However, histological evidence of lung injury (lung injury score mean difference = -0.07; P = 0.04) and BAL IL-8 were reduced. In addition, hMSC-treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in transmembrane oxygenator pressure gradients. This was accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers.Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during venovenous ECMO.
Rationale: Mesenchymal stromal cell (MSC) therapy is a promising intervention for acute respiratory distress syndrome (ARDS), although trials to date have not investigated its use alongside extracorporeal membrane oxygenation (ECMO). Recent preclinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO. Objectives: To determine the safety and efficacy of MSC therapy in a model of ARDS and ECMO. Methods: ARDS was induced in 14 sheep, after which they were established on venovenous ECMO. Subsequently, they received either endobronchial induced pluripotent stem cell-derived human MSCs (hMSCs) (n = 7) or cell-free carrier vehicle (vehicle control; n = 7). During ECMO, a low Vt ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analyzed, in addition to continuous respiratory and hemodynamic monitoring.Measurements and Main Results: The administration of hMSCs did not improve oxygenation (PaO2/FiO2 mean difference = -146 mm Hg; P = 0.076) or pulmonary function. However, histological evidence of lung injury (lung injury score mean difference = -0.07; P = 0.04) and BAL IL-8 were reduced. In addition, hMSC-treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in transmembrane oxygenator pressure gradients. This was accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers.Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during venovenous ECMO.
Authors: M Dominici; K Le Blanc; I Mueller; I Slaper-Cortenbach; Fc Marini; Ds Krause; Rj Deans; A Keating; Dj Prockop; Em Horwitz Journal: Cytotherapy Date: 2006 Impact factor: 5.414
Authors: Barbara A Christy; Maryanne C Herzig; Robbie K Montgomery; Christopher Delavan; James A Bynum; Kristin M Reddoch; Andrew P Cap Journal: J Trauma Acute Care Surg Date: 2017-07 Impact factor: 3.313
Authors: Alexandre Biasi Cavalcanti; Érica Aranha Suzumura; Ligia Nasi Laranjeira; Denise de Moraes Paisani; Lucas Petri Damiani; Helio Penna Guimarães; Edson Renato Romano; Marisa de Moraes Regenga; Luzia Noriko Takahashi Taniguchi; Cassiano Teixeira; Roselaine Pinheiro de Oliveira; Flavia Ribeiro Machado; Fredi Alexander Diaz-Quijano; Meton Soares de Alencar Filho; Israel Silva Maia; Eliana Bernardete Caser; Wilson de Oliveira Filho; Marcos de Carvalho Borges; Priscilla de Aquino Martins; Mirna Matsui; Gustavo Adolfo Ospina-Tascón; Thiago Simões Giancursi; Nelson Dario Giraldo-Ramirez; Silvia Regina Rios Vieira; Maria da Graça Pasquotto de Lima Assef; Mohd Shahnaz Hasan; Wojciech Szczeklik; Fernando Rios; Marcelo Britto Passos Amato; Otávio Berwanger; Carlos Roberto Ribeiro de Carvalho Journal: JAMA Date: 2017-10-10 Impact factor: 56.272
Authors: Megan V Jackson; Thomas J Morrison; Declan F Doherty; Daniel F McAuley; Michael A Matthay; Adrien Kissenpfennig; Cecilia M O'Kane; Anna D Krasnodembskaya Journal: Stem Cells Date: 2016-04-29 Impact factor: 6.277
Authors: Manoj M Lalu; Katrina J Sullivan; Shirley Hj Mei; David Moher; Alexander Straus; Dean A Fergusson; Duncan J Stewart; Mazen Jazi; Malcolm MacLeod; Brent Winston; John Marshall; Brian Hutton; Keith R Walley; Lauralyn McIntyre Journal: Elife Date: 2016-11-17 Impact factor: 8.140
Authors: Mark J D Griffiths; Danny Francis McAuley; Gavin D Perkins; Nicholas Barrett; Bronagh Blackwood; Andrew Boyle; Nigel Chee; Bronwen Connolly; Paul Dark; Simon Finney; Aemun Salam; Jonathan Silversides; Nick Tarmey; Matt P Wise; Simon V Baudouin Journal: BMJ Open Respir Res Date: 2019-05-24
Authors: Nayra Cardenes; Paola Aranda-Valderrama; Jonathan P Carney; Jacobo Sellares Torres; Diana Alvarez; Ergin Kocyildirim; Julie A Wolfram Smith; Antony E Ting; Luigi Lagazzi; Zheming Yu; Scott Mason; Ernesto Santos; Brian J Lopresti; Mauricio Rojas Journal: BMJ Open Respir Res Date: 2019-01-12
Authors: Karin Wildi; Kieran Hyslop; Jonathan Millar; Samantha Livingstone; Margaret R Passmore; Mahé Bouquet; Emily Wilson; Gianluigi LiBassi; John F Fraser; Jacky Y Suen Journal: Front Med (Lausanne) Date: 2022-07-05
Authors: Robinder G Khemani; Jessica T Lee; David Wu; Edward J Schenck; Margaret M Hayes; Patricia A Kritek; Gökhan M Mutlu; Hayley B Gershengorn; Rémi Coudroy Journal: Am J Respir Crit Care Med Date: 2021-05-01 Impact factor: 21.405
Authors: Louise E See Hoe; Karin Wildi; Nchafatso G Obonyo; Nicole Bartnikowski; Charles McDonald; Kei Sato; Silver Heinsar; Sanne Engkilde-Pedersen; Sara Diab; Margaret R Passmore; Matthew A Wells; Ai-Ching Boon; Arlanna Esguerra; David G Platts; Lynnette James; Mahe Bouquet; Kieran Hyslop; Tristan Shuker; Carmen Ainola; Sebastiano M Colombo; Emily S Wilson; Jonathan E Millar; Maximillian V Malfertheiner; Janice D Reid; Hollier O'Neill; Samantha Livingstone; Gabriella Abbate; Noriko Sato; Ting He; Viktor von Bahr; Sacha Rozencwajg; Liam Byrne; Leticia P Pimenta; Lachlan Marshall; Lawrie Nair; John-Paul Tung; Jonathan Chan; Haris Haqqani; Peter Molenaar; Gianluigi Li Bassi; Jacky Y Suen; David C McGiffin; John F Fraser Journal: Intensive Care Med Exp Date: 2021-12-24