RETRACTED: Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality (Retracted article. See vol. 117, pg. 7188, 2011)

被引:71
作者
Niessen, Frank [1 ]
Furlan-Freguia, Christian [1 ]
Fernandez, Jose A. [2 ]
Mosnier, Laurent O. [2 ]
Castellino, Francis J. [3 ]
Weiler, Hartmut [4 ]
Rosen, Hugh [1 ,5 ]
Griffin, John H. [2 ]
Ruf, Wolfram [1 ]
机构
[1] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[3] Univ Notre Dame, Notre Dame, IN 46556 USA
[4] Blood Ctr Wisconsin, Milwaukee, WI USA
[5] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED PROTEIN-C; DISSEMINATED INTRAVASCULAR COAGULATION; TISSUE FACTOR; ESCHERICHIA-COLI; MOUSE MODEL; SPHINGOSINE KINASE-1; HEMOSTATIC BALANCE; COUPLED RECEPTOR; MICE DEFICIENT; SEVERE SEPSIS;
D O I
10.1182/blood-2008-12-192385
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 sub-types determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo. (Blood. 2009;113:2859-2866)
引用
收藏
页码:2859 / 2866
页数:8
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