Diana Islam1,2, Yongbo Huang1, Vito Fanelli2,3, Luisa Delsedime4, Sulong Wu1, Julie Khang1,2, Bing Han1,2, Alice Grassi2, Manshu Li1,2, Yonghao Xu1,2, Alice Luo1,2, Jianfeng Wu2, Xiaoqing Liu1, Montey McKillop5, Jeffery Medin5, Haibo Qiu6, Nanshan Zhong1,2, Mingyao Liu7,8,9, John Laffey10, Yimin Li1,2, Haibo Zhang1,2,8,9,11,12. 1. 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 2. 2 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada. 3. 3 Department of Anesthesia and Critical Care and. 4. 4 Department of Pathology, University of Turin, Turin, Italy. 5. 5 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin. 6. 6 Department of Critical Care Medicine, Zhongda Hospital, Southeast University, Nanjing, China. 7. 7 Department of Surgery, University Health Network, Toronto, Ontario, Canada. 8. 8 Department of Medicine. 9. 9 Department of Physiology. 10. 10 Department of Anesthesia and Intensive Care Medicine, National University of Ireland, Galway, Ireland. 11. 11 Interdepartmental Division of Critical Care Medicine, and. 12. 12 Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada; and.
Abstract
Rationale: There are controversial reports on applications of mesenchymal stromal cells (MSCs) in patients with acute respiratory distress syndrome (ARDS). Objectives: We hypothesized that lung microenvironment was the main determinant of beneficial versus detrimental effects of MSCs during ARDS. Methods: Lung proteome was profiled in three models of injury induced by acid instillation and/or mechanical ventilation in mice. Human gene of glutathione peroxidase-1 was delivered before MSC administration; or MSCs carrying human gene of IL-10 or hepatocyte growth factor were administered after lung injury. An inhibitory cocktail against IL-6, fibronectin, and oxidative stress was used in in vitro studies using human small airway epithelial cells and human MSCs after exposure to plasma of patients with ARDS. Measurements and Main Results: Distinct proteomic profiles were observed in three lung injury models. Administration of MSCs protected lung from ventilator-induced injury, whereas it worsened acid-primed lung injuries associated with fibrotic development in lung environment that had high levels of IL-6 and fibronectin along with low antioxidant capacity. Correction of microenvironment with glutathione peroxidase-1, or treatment with MSCs carrying human gene of IL-10 or hepatocyte growth factor after acid-primed injury, reversed the detrimental effects of native MSCs. Proteomic profiles obtained in the mouse models were also similarly observed in human ARDS. Treatment with the inhibitory cocktail in samples of patients with ARDS retained protective effects of MSCs in small airway epithelial cells. Conclusions: MSCs can be beneficial or detrimental depending on microenvironment at the time of administration. Identification of potential beneficiaries seems to be crucial to guide MSC therapy in ARDS.
Rationale: There are controversial reports on applications of mesenchymal stromal cells (MSCs) in patients with acute respiratory distress syndrome (ARDS). Objectives: We hypothesized that lung microenvironment was the main determinant of beneficial versus detrimental effects of MSCs during ARDS. Methods: Lung proteome was profiled in three models of injury induced by acid instillation and/or mechanical ventilation in mice. Human gene of glutathione peroxidase-1 was delivered before MSC administration; or MSCs carrying human gene of IL-10 or hepatocyte growth factor were administered after lung injury. An inhibitory cocktail against IL-6, fibronectin, and oxidative stress was used in in vitro studies using human small airway epithelial cells and human MSCs after exposure to plasma of patients with ARDS. Measurements and Main Results: Distinct proteomic profiles were observed in three lung injury models. Administration of MSCs protected lung from ventilator-induced injury, whereas it worsened acid-primed lung injuries associated with fibrotic development in lung environment that had high levels of IL-6 and fibronectin along with low antioxidant capacity. Correction of microenvironment with glutathione peroxidase-1, or treatment with MSCs carrying human gene of IL-10 or hepatocyte growth factor after acid-primed injury, reversed the detrimental effects of native MSCs. Proteomic profiles obtained in the mouse models were also similarly observed in human ARDS. Treatment with the inhibitory cocktail in samples of patients with ARDS retained protective effects of MSCs in small airway epithelial cells. Conclusions: MSCs can be beneficial or detrimental depending on microenvironment at the time of administration. Identification of potential beneficiaries seems to be crucial to guide MSC therapy in ARDS.
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