Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia

Sven Asmussen, Hiroshi Ito, Daniel L. Traber, Jae W. Lee, Robert A. Cox, Hal K. Hawkins, Daniel F. McAuley, David H. McKenna, Lillian D. Traber, Hanjing Zhuo, Jennifer Wilson, David Herndon, Donald Prough, Kathleen D. Liu, Michael A. Matthay, Perenlei Enkhbaatar

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Abstract

Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.51011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 9715 mm Hg; lower dose: 28855 mm Hg (p=0.003); higher dose: 3272 mm Hg ( p=0.003)). The median lung water content was lower in the higher-dose hMSCtreated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] ( p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS.9999.

Original languageEnglish (US)
Pages (from-to)819-825
Number of pages7
JournalThorax
Volume69
Issue number9
DOIs
StatePublished - 2014

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Bacterial Pneumonia
Acute Lung Injury
Mesenchymal Stromal Cells
Sheep
Control Groups
Adult Respiratory Distress Syndrome
Pulmonary Edema
Lung
Insufflation
Isoflurane
Smoke
Pseudomonas aeruginosa
Anesthesia
Bone Marrow
Escherichia coli
Bacteria
Survival
Water
Wounds and Injuries
Therapeutics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. / Asmussen, Sven; Ito, Hiroshi; Traber, Daniel L.; Lee, Jae W.; Cox, Robert A.; Hawkins, Hal K.; McAuley, Daniel F.; McKenna, David H.; Traber, Lillian D.; Zhuo, Hanjing; Wilson, Jennifer; Herndon, David; Prough, Donald; Liu, Kathleen D.; Matthay, Michael A.; Enkhbaatar, Perenlei.

In: Thorax, Vol. 69, No. 9, 2014, p. 819-825.

Research output: Contribution to journalArticle

Asmussen, S, Ito, H, Traber, DL, Lee, JW, Cox, RA, Hawkins, HK, McAuley, DF, McKenna, DH, Traber, LD, Zhuo, H, Wilson, J, Herndon, D, Prough, D, Liu, KD, Matthay, MA & Enkhbaatar, P 2014, 'Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia', Thorax, vol. 69, no. 9, pp. 819-825. https://doi.org/10.1136/thoraxjnl-2013-204980
Asmussen, Sven ; Ito, Hiroshi ; Traber, Daniel L. ; Lee, Jae W. ; Cox, Robert A. ; Hawkins, Hal K. ; McAuley, Daniel F. ; McKenna, David H. ; Traber, Lillian D. ; Zhuo, Hanjing ; Wilson, Jennifer ; Herndon, David ; Prough, Donald ; Liu, Kathleen D. ; Matthay, Michael A. ; Enkhbaatar, Perenlei. / Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. In: Thorax. 2014 ; Vol. 69, No. 9. pp. 819-825.
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abstract = "Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.51011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 9715 mm Hg; lower dose: 28855 mm Hg (p=0.003); higher dose: 3272 mm Hg ( p=0.003)). The median lung water content was lower in the higher-dose hMSCtreated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] ( p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS.9999.",
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AU - Asmussen, Sven

AU - Ito, Hiroshi

AU - Traber, Daniel L.

AU - Lee, Jae W.

AU - Cox, Robert A.

AU - Hawkins, Hal K.

AU - McAuley, Daniel F.

AU - McKenna, David H.

AU - Traber, Lillian D.

AU - Zhuo, Hanjing

AU - Wilson, Jennifer

AU - Herndon, David

AU - Prough, Donald

AU - Liu, Kathleen D.

AU - Matthay, Michael A.

AU - Enkhbaatar, Perenlei

PY - 2014

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N2 - Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.51011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 9715 mm Hg; lower dose: 28855 mm Hg (p=0.003); higher dose: 3272 mm Hg ( p=0.003)). The median lung water content was lower in the higher-dose hMSCtreated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] ( p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS.9999.

AB - Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.51011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 9715 mm Hg; lower dose: 28855 mm Hg (p=0.003); higher dose: 3272 mm Hg ( p=0.003)). The median lung water content was lower in the higher-dose hMSCtreated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] ( p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS.9999.

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