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PLoS One. 2017 Nov 8;12(11):e0187637. doi: 10.1371/journal.pone.0187637. eCollection 2017.

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

Liu YY1,2,3, Chiang CH1,2,4, Hung SC3,5,6,7,8, Chian CF9, Tsai CL9, Chen WC1,2, Zhang H10.

Author information

1
Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.
2
Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
3
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
4
Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
5
Integrative Stem Cell Center, Chinese Medical University Hospital, Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
6
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
7
Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.
8
Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan.
9
Division of Pulmonary and Critical Care Medicine, Internal Medicine Department, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
10
Department of Physiology, and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
29117205
PMCID:
PMC5678873
DOI:
10.1371/journal.pone.0187637
[Indexed for MEDLINE]
Free PMC Article

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