Impact of Microvesicles Pro‐Inflammatory Properties on Sepsis‐Induced Endothelium Dysfunction

This is the first inter‐disciplinary proposal to assess the impact of microvesicles (MVs)‐ pro‐inflammatory properties on sepsis‐induced endothelial dysfunction. Sepsis is a clinical syndrome characterized by a systemic inflammatory response to infection, leading to endothelial dysfunction with increased endothelial permeability, increased levels of nitric oxide (NO), reduced NO availability, enhanced reactive oxygen species (ROS)‐induced oxidative stress and disseminated intravascular coagulation with microvascular thrombosis.The overall goal of this research proposal was to assess phenotypic and pathophysiological implications of pro‐inflammatory MVs as strong biomarkers of sepsis‐induced vascular dysfunction over a 6 hour time course. We hypothesize that the pro‐inflammatory effects of isolated and characterized MVs from septic rats are tissue and time course‐specific. Ten rats were instrumented under isoflurane anesthesia to implant Tygon catheters into the femoral artery and vein to record mean arterial blood pressure (MAP), heart rate and for drug administration, respectively. Following recovery from surgery, rats were injected with lipopolysaccharide (LPS) at 20 mg/kg IV. Simultaneously to hemodynamic measurements, blood samples were collected from control (n=5) and experimental animals (n=5) into 0.129 mol/L sodium citrate to isolate and characterize leucocytes MVs and platelet MVs. Along with decreases in MAP, preliminary data show that LPS administration induced increases in MV counts (PMVs and LMVs) 4 hrs following LPS administration. LMVs increased from 39/μl to 68/μl and PMVs increased from 145/μl to 631/μl. We are currently exploring endothelial MVs in rat plasma subjected to LPS. This on‐going project is important because it will answer a critical question not explored until now: How the vascular system is affected in sepsis and consequently what will be the best treatment to improve endothelial dysfunction and clinical outcomes.