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Human induced pluripotent stem cells ameliorate hyperoxia-induced lung injury in a mouse model.

ABSTRACT: Hyperoxia-induced lung injury occurs in neonates on oxygen support due to premature birth, often leading to the development of bronchopulmonary dysplasia. Current treatment options have limited effect. The aim of this study was to determine if human induced pluripotent stem cells (iPSCs) and those differentiated to an alveolar-like phenotype (diPSCs) could repair hyperoxia-induced lung damage in a mouse model. Neonatal C57BL6/J mice were separated into two groups and exposed to 75% oxygen over 6 or 14 days. Cell treatments were instilled intra-orally following removal. Controls included hyperoxia, normoxia, and a vehicle. 7 and 14 days post treatment, lungs were extracted and histomorphometric analysis performed. Gene expression of markers mediating inflammation (Tgf?1, Nfkb1, and Il-6) were investigated. In addition, exosomes from each cell type were isolated and administered as a cell free alternative. There was a significant difference between the mean linear intercept (MLI) in hyperoxic vs. normoxic lungs prior to treatment. No difference existed between the MLI in iPSC-treated lungs vs. normoxic lungs after 6 and 14 days of hyperoxia. For mice exposed to 6 days of hyperoxia, gene expression in iPSC-treated lungs returned to normal 14 days later. At the same time points, diPSCs were not as effective. Exosomes were also not as effective in reversing hyperoxic lung damage as their cellular counterparts. This study highlights the potential benefit of using iPSCs to repair damaged lung tissue through possible modulation of the inflammatory response, leading to novel therapies for acute hyperoxia-induced lung injury and the prevention of bronchopulmonary dysplasia.

SUBMITTER: Mitchell A

PROVIDER: S-EPMC7013222 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Human induced pluripotent stem cells ameliorate hyperoxia-induced lung injury in a mouse model.

Mitchell Adam A Wanczyk Heather H Jensen Todd T Finck Christine C

American journal of translational research 20200115 1

Hyperoxia-induced lung injury occurs in neonates on oxygen support due to premature birth, often leading to the development of bronchopulmonary dysplasia. Current treatment options have limited effect. The aim of this study was to determine if human induced pluripotent stem cells (iPSCs) and those differentiated to an alveolar-like phenotype (diPSCs) could repair hyperoxia-induced lung damage in a mouse model. Neonatal C57BL6/J mice were separated into two groups and exposed to 75% oxygen over 6 ...[more]

PMID: 32051754

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Project description:An important issue in critical care medicine is the identification of ways to protect the lungs from oxygen toxicity and reduce systemic oxidative stress in conditions requiring mechanical ventilation and high levels of oxygen. One way to prevent oxygen toxicity is to augment antioxidant enzyme activity in the respiratory system. The current study investigated the ability of aerosolized extracellular superoxide dismutase (EC-SOD) to protect the lungs from hyperoxic injury. Recombinant human EC-SOD (rhEC-SOD) was produced from a synthetic cassette constructed in the methylotrophic yeast Pichia pastoris. Female CD-1 mice were exposed in hyperoxia (FiO2>95%) to induce lung injury. The therapeutic effects of EC-SOD and copper-zinc SOD (CuZn-SOD) via an aerosol delivery system for lung injury and systemic oxidative stress at 24, 48, 72 and 96 h of hyperoxia were measured by bronchoalveolar lavage, wet/dry ratio, lung histology, and 8-oxo-2'-deoxyguanosine (8-oxo-dG) in lung and liver tissues. After exposure to hyperoxia, the wet/dry weight ratio remained stable before day 2 but increased significantly after day 3. The levels of oxidative biomarker 8-oxo-dG in the lung and liver were significantly decreased on day 2 (P<0.01) but the marker in the liver increased abruptly after day 3 of hyperoxia when the mortality increased. Treatment with aerosolized rhEC-SOD increased the survival rate at day 3 under hyperoxia to 95.8%, which was significantly higher than that of the control group (57.1%), albumin treated group (33.3%), and CuZn-SOD treated group (75%). The protective effects of EC-SOD against hyperoxia were further confirmed by reduced lung edema and systemic oxidative stress. Aerosolized EC-SOD protected mice against oxygen toxicity and reduced mortality in a hyperoxic model. The results encourage the use of an aerosol therapy with EC-SOD in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure, including acute respiratory distress syndrome (ARDS).

Project description: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.

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Human induced pluripotent stem cells ameliorate hyperoxia-induced lung injury in a mouse model.

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Human induced pluripotent stem cells ameliorate hyperoxia-induced lung injury in a mouse model.

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