cytochrome-c-t and Pulmonary-Embolism

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.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Bronchoalveolar Lavage Fluid; Capillaries; Caspase 3; Cell Hypoxia; Cytochromes c; Cytosol; Glutathione; Hemodynamics; Hydrogen Peroxide; Intercellular Adhesion Molecule-1; Leukocyte Count; Lung Injury; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mitogen-Activated Protein Kinases; NF-kappa B; Organ Size; Peroxidase; Protein Carbonylation; Proto-Oncogene Proteins c-bcl-2; Pulmonary Embolism; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Thiobarbituric Acid Reactive Substances; Thrombosis; Vascular Cell Adhesion Molecule-1