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

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 adminis...

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Bibliographic Details
Published in:PloS one 2017-11, Vol.12 (11), p.e0187637-e0187637
Main Authors: Liu, Yung-Yang, Chiang, Chi-Huei, Hung, Shih-Chieh, Chian, Chih-Feng, Tsai, Chen-Liang, Chen, Wei-Chih, Zhang, Haibo
Format: Article
Language:English
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0187637