Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury

• Published in: PloS one Vol. 12; no. 11; p. e0187637
• Main Authors: Liu, Yung-Yang, Chiang, Chi-Huei, Hung, Shih-Chieh, Chian, Chih-Feng, Tsai, Chen-Liang, Chen, Wei-Chih, Zhang, Haibo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-11-2017; Public Library of Science (PLoS)
• Subjects: Alveoli; Angiogenesis; Animals; Antioxidants - metabolism; Apoptosis; Bcl-2 protein; Biology and Life Sciences; Biomarkers - metabolism; Bone marrow; Bronchoalveolar Lavage Fluid; Capillaries - pathology; Capillaries - physiopathology; Care and treatment; Caspase 3 - metabolism; Cell Hypoxia; Clinical medicine; Critical care; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Cytokines; Cytosol - metabolism; Development and progression; Drug dosages; Edema; Embolism; Embolisms; Glutathione; Glutathione - metabolism; Hemodynamics; Hydrogen Peroxide - metabolism; Hypoxia; Inflammation; Injuries; Intercellular Adhesion Molecule-1 - metabolism; Interleukin 10; Internal medicine; Ischemia; Laboratory animals; Leukocyte Count; Lung Injury - complications; Lung Injury - pathology; Lung Injury - physiopathology; Lung Injury - therapy; Lungs; Male; MAP kinase; Medicine; Medicine and Health Sciences; Membrane permeability; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchyme; Mitochondria; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; NF-κB protein; Organ Size; Oxygen; Permeability; Peroxidase - metabolism; Physiological aspects; Preconditioning; Prevention; Properties; Prostaglandin E2; Protein Carbonylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pulmonary Embolism - complications; Pulmonary Embolism - pathology; Pulmonary Embolism - physiopathology; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reperfusion; Reperfusion injury; Reperfusion Injury - complications; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Reperfusion Injury - therapy; Risk factors; Rodents; Signal Transduction; Signaling; Skin & tissue grafts; Stem cell transplantation; Stem cells; Thiobarbituric Acid Reactive Substances - metabolism; Thromboembolism; Thrombosis; Thrombosis - pathology; Thrombosis - physiopathology; Transplants & implants; Vascular Cell Adhesion Molecule-1 - metabolism; Ventilation; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187637

Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.
I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.
I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.
Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.