J. V. Martin1, D. M. Liberati1, L. N. Diebel1 1Wayne State University,Surgery/School Of Medicine,Detroit, MI, USA
Introduction: Stress related hyperglycemia is associated with poor outcomes in trauma and critically ill patients. Correction of hyperglycemia may improve clinical outcomes; however tight glycemic control with insulin may lead to hypoglycemic episodes and resultant glucose variability. Metformin has demonstrated efficiency in hyperglycemia treatment in burn and non-diabetic coronary bypass surgery patients. These effects may be partly due to non-glycemic effects including a beneficial effect on endothelial function. We have shown that acute hyperglycemia exacerbates trauma induced endothelial and glycocalyx injury in an in vitro model. We therefore studied the effect of metformin on endothelial injury in a biomimetic model of hemorrhagic shock using a microfluidic device.
Methods: Human umbilical vein endothelial cell (HUVEC) monolayers were established and perfused in a microfluidic device. Perfusion conditions included media alone (control), media + 80 or 200 mg/dl glucose with or without hypoxia-reoxygenation (H/R) + epinephrine (Epi) to mimic the microcirculation following hemorrhagic shock (HS). Metformin (50µM) was added after glucose exposure. Markers of endothelial glycocalyx degradation were syndecan-1 (syn-1) and hyaluronic acid (HLA) shedding. Endothelial cell activation markers included soluble thrombomodulin (sTM), and angiopoietin-1 and 2 concentrations in the perfusate. Reactive oxygen species (ROS) and inducible nitric oxidase synthase (iNOS) generation were measured using fluorescent imaging.
Results: See Table.
Conclusion: Metformin ameliorated stress hyperglycemia effects on glycocalyx and vascular barriers in a biomimetic model of the microcirculation following HS. These effects may be related to decreased ROS and iNOS generation. Microfluidics may be useful to study the endotheliopathy of trauma and HS.
