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 (2.5×1011 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, 5×106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×106 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. Trail registration number NCT01775774 for Phase 1. NCT02097641 for Phase 2.

Therapeutic Potential of Mesenchymal Stromal Cells for Acute Respiratory Distress Syndrome

“…In addition, the degree of pulmonary edema was lower in the sheep treated with the higher dose of MSCs compared with the control group ( Table 2). These studies provided reassurance in a clinically relevant large animal model that the MSCs were likely to be safe and also reinforced the possibility that they might be effective in the clinical setting of ARDS (16).…”

Mesenchymal stem cells and infectious diseases: Smarter than drugs

“…Human MSCs improved oxygenation and decreased pulmonary edema in a sheep model of Adult Respiratory Distress Syndrome (ARDS) [35]. Gram-negative pathogens are not the only pathogens that can be treated with MSC therapy.…”

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…80 All of these gaps in knowledge underscore a pressing need to validate candidate mechanisms in reproducible in-vivo models and for improved characterisation of bioactive factors and their mode of action. 79 Two studies 84,85 in sheep models of ARDS have lent support to the safety and potential effi cacy of MSC therapy. A small randomised trial of adipose-derived MSCs in 12 patients with ARDS in China is the fi rst to suggest that MSCs can be safely given to patients with ARDS.…”