Abstract
Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)-dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Animals
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Capillary Leak Syndrome / etiology
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Capillary Leak Syndrome / physiopathology
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Capillary Leak Syndrome / prevention & control*
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Capillary Permeability / drug effects
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Capillary Permeability / genetics
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Capillary Permeability / physiology*
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Disseminated Intravascular Coagulation / physiopathology*
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Endothelial Protein C Receptor
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Endothelium, Vascular / physiopathology
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Endotoxins / toxicity
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Enzyme Activation
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Glycoproteins / physiology*
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Hirudins / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / physiology
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Protein C / genetics
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Protein C / physiology*
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Receptor, PAR-1 / deficiency
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Receptor, PAR-1 / genetics
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Receptor, PAR-1 / physiology*
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Receptors, Cell Surface
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Receptors, Lysosphingolipid / deficiency
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / physiology
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Signal Transduction
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Specific Pathogen-Free Organisms
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Sphingosine-1-Phosphate Receptors
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Systemic Inflammatory Response Syndrome / chemically induced
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Systemic Inflammatory Response Syndrome / complications
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Systemic Inflammatory Response Syndrome / physiopathology*
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Thiophenes / pharmacology
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Thrombin / antagonists & inhibitors
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Thrombin / physiology
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Thromboplastin / physiology
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beta-Alanine / analogs & derivatives
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beta-Alanine / pharmacology
Substances
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AUY 954
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Endothelial Protein C Receptor
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Endotoxins
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Glycoproteins
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Hirudins
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Nerve Tissue Proteins
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Procr protein, mouse
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Protein C
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Receptor, PAR-1
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Receptors, Cell Surface
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Receptors, Lysosphingolipid
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S1pr3 protein, mouse
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Sip1 protein, mouse
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Sphingosine-1-Phosphate Receptors
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Thiophenes
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beta-Alanine
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endotoxin, Escherichia coli
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Thromboplastin
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Thrombin