The Roles of Glutamine on the Repair of Endothelial Cell Injury and the Function of Progenitor Cells in Septic Mice

Sepsis-induced endothelial cell (EC) injury is known to be one of the main causes that lead to remote organ dysfunction. Overexpression of pro-inflammatory cytokines result from sepsis dysregulate the balance of von Willebrand factor (vWF)/A Disintegrin and Metalloprotease with Thrombo Spondin (ADAMTS)13 system and thus activate capillary platelet aggregation and induce organ ischemia. Besides, the alteration of angiopoietin/Tie2 ligand-receptor system in EC downregulate the activity of endothelial nitric oxide synthase and VE-cadherin expression that may increase endothelial permeability and accelerate the apoptosis of EC. Endothelial progenitor cell (EPC)s are circulating endothelial precursor cells associated with sepsis. Recent study demonstrated that circulating EPCs were increased in septic patients while non-survivors had significantly lower numbers of EPCs than survivors. Animal study showed that facilitate EPC recruitment promote the repair of EC and exogenous EPC administration improve the survival in sepsis. Glutamine (GLN) is a specific nutrient with immunomodulatory properties. GLN is considered as essential amino acid following critical illness and injury. Previous studies showed that GLN attenuated oxidative stress and reduce infectious complications in trauma patients. Studies performed by our laboratory also found that GLN balanced the T cell polarization and alleviate the inflammation and damage of organs induced by sepsis. However, no study investigates the role of GLN on the regulation on EPC in sepsis. Also, the synergistic effect of GLN with different dose of EPC on tissue injury in sepsis remains unknown and require investigation. We plan to carry out this study in 3 consecutive years. In 1st year, mice are subjected to cecal ligation and puncture (CLP) and GLN will be administered to evaluate the expression of blood EPC in association with the EC function, adhesion molecule expressions and tissue injury. In the 2nd year, stem cells obtained from mice bone marrow will be cultured and differentiate to EPC. Different dosages of GLN will be cultured with EPC to evaluate the rd optimal condition for EPC proliferation and function. In the 3 year, the optimal conditioned EPC accompanied with GLN will be administered to CLP mice to evaluate whether exogenously EPC and GLN may have synergistic effects in improving EC function and thus attenuating organ injury in sepsis. This study will be the first study to investigate the effect of GLN on EPC regulation, and the results may provide useful information in clinical application in nutrition support and medical therapy in septic condition.