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

Yung-Yang Liu,Chi-Huei Chiang,Chih-Feng Chian,Wei-Chih Chen,Haibo Zhang,Chen-Liang Tsai,Shih-Chieh Hung,Guo-Chang Fan

doi:10.1371/journal.pone.0187637

Abstract

BackgroundHypoxia 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.MethodsI/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.ResultsI/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.ConclusionsHypoxic 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.

Highlights

Ischemia/reperfusion (I/R) injury is a common clinical problem encountered in lung transplantation, resuscitation from shock and cardiac surgery
The administration of a low dose of hypoxic mesenchymal stem cells (MSCs) effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of reactive oxygen species (ROS) and anti-apoptosis effect, this effect was not observed with a high dose of hypoxic MSCs
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

Summary

Introduction

Ischemia/reperfusion (I/R) injury is a common clinical problem encountered in lung transplantation, resuscitation from shock and cardiac surgery. With regards to the molecular mechanisms of I/R lung injury, it has been proposed that I/R can activate cellular transduction [1] resulting in the generation of reactive oxygen species (ROS), nuclear factor-kappa B (NF-κB) translocation, production of inflammatory cytokines [2,3,4,5,6] and the upregulation of cell surface co-stimulatory molecules [7,8,9,10] This sequence is followed by more inflammatory cells being recruited into the interstitium and alveoli. 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

Results

Conclusion