ABSTRACT
Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.
Subject(s)
Blood Platelets , Human Umbilical Vein Endothelial Cells , Sepsis , von Willebrand Factor , Animals , Sepsis/drug therapy , von Willebrand Factor/metabolism , Humans , Mice , Human Umbilical Vein Endothelial Cells/drug effects , Male , Blood Platelets/drug effects , Blood Platelets/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Integrin alphaVbeta3/metabolism , Integrin alphaVbeta3/antagonists & inhibitors , Capillary Permeability/drug effectsABSTRACT
<p><b>OBJECTIVE</b>To explore the value of lower-limb short latency somatosensory evoked potentials (SLSEP) in predicting early death in patients with massive cerebral infarction.</p><p><b>METHODS</b>Forty-eight patients of massive cerebral infarction were admitted in the Neurological Intensive Care Unit (NICU) between March 2008 and March 2009, and Glasgow-Pittsburgh coma scale (GPCS) and SLSEP were recorded and graded within 24 h after admission. The patients were divided into survival and death groups (including brain death) according to their short-term prognosis. The correlations of SLSEP and GPCS to the mortality were assessed.</p><p><b>RESULTS</b>A significant correlation was found between SLSEP and the mortality in patients with massive cerebral infarction (r=0.484, P<0.001). The positive predictive value of the SLSEP grade 3 to death was 100%, and the patients with malignant middle cerebral artery infarction (mMCAI) appeared to have a 100% mortality.</p><p><b>CONCLUSION</b>SLSEP grade 3 can be a highly specificity in predicting early death in patients with massive cerebral infarction, and it is also of value in determining the timing of surgical intervention of mMCAI.</p>
