How hepatocytes protect against vascular disease

JAMEY MARTH; PRABHJIT GREWAL; WON HO YANG; CHERI MANN; DAVID DITTO; RICARDO LARDONE; NISSI VARKI; DZUNG LE

Munich

Congreso; Joint Meeting 'European Society of Microcirculation (ESM)' and 'German Society of Microcirculation and Vascular Biology (GfMVB)'; 2011

European Society of Microcirculation (ESM) and German Society of Microcirculation and Vascular Biology (GfMVB)

The Ashwell-Morell receptor (AMR) of hepatocytes rapidly clears from blood circulation exogenously administered glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. Although the AMR is conserved throughout mammalian radiation, endogenous ligands and a biological purpose of this prototypical receptor and lectin have only recently been discovered. We previously identified circulating platelets and von Willebrand factor (VWF) as endogenous AMR ligands and found that up to 70% of blood platelets are rapidly removed from circulation by the AMR during early sepsis induced by Streptococcus pneumoniae (SPN) infection. This AMR-dependent platelet clearance activity is induced during SPN infection by the SPN-encoded NanA neuraminidase. Hemostatic adaptation by the AMR reduces the onset of disseminated intravascular coagulation (DIC) - a lethal complication of sepsis, and significantly improves the probability of host survival. Therefore our findings challenge the assumption that the early thrombocytopenia of sepsis, which is typically a clinical hallmark of infection, is due to the consumption of coagulation factors, and instead indicate that AMR-mediated platelet clearance is a host response to reduce the onset and severity of DIC. We have now developed an approach towards further discovery of novel AMR ligands in vivo and to determine the role of vascular glycoprotein clearance in the therapeutic activity of the AMR during sepsis. Our findings indicate that engagement of the AMR early during infection by intravenous administration of neuraminidase promotes a selective and transient hypo-thrombotic state that requires platelet clearance and which minimizes disseminated intravascular coagulopathy while greatly increasing the frequency of host survival. At present, there are no therapeutic agents in the clinic with similar anti- septic therapeutic potency, and which can diminish organ damage and failure. Neuraminidase-induced AMR clearance activity appears to provide an effective anticoagulant therapy for multiple indications including preservation of organ health and function during the onset and progression of sepsis.