title: Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia.
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 (2.5×10(11) 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, 5×10(6) hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×10(6) 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 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated 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.
  
  
  BACKGROUND
  NCT01775774 for Phase 1. NCT02097641 for Phase 2.
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Asmussen
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA.
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA Centre for Infection and Immunity, The Queen's University of Belfast, Belfast, Northern Ireland, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Production Assistance in Cellular Therapy, University of Minnesota, Saint Paul, Minnesota, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: McKenna
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA.
authors.forename: Hanjing
authors.initials: H
authors.lastname: Zhuo
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Shriners Hospital for Children, Galveston, Texas, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Prough
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Departments of Medicine & Anesthesiology, Cardiovascular Research Institute, The University of California San Francisco, San Francisco, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D006439:Hemodynamics; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology; D007958:Leukocyte Count; D045164:Mesenchymal Stem Cell Transplantation; D009504:Neutrophils; D018410:Pneumonia, Bacterial / Q000150:complications*; D011552:Pseudomonas Infections / Q000150:complications*; D011550:Pseudomonas aeruginosa; D011654:Pulmonary Edema / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy*; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications; D014882:Water-Electrolyte Balance
chemical_list: D001219:Aspartate Aminotransferases
keywords: ARDS