Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis

Abstract

As one of the virulence factors of Bacillus anthracis, lethal toxin (LT) induces various pathogenic responses including the suppression of the coagulation system. In this study, we observed that LT markedly increased the circulating soluble P-selectin (sP-sel) levels and microparticle (MP) count in wild-type but not P-selectin (P-sel, Selp¡/¡ ) knockout mice. Because sP-sel induces a hypercoagulable state through PSGL-1 pathway to generate tissue factorpositive MPs, we hypothesized that the increase in plasma sP-sel levels can be a self-rescue response in hosts against the LT-mediated suppression of the coagulation system. In agreement with our hypothesis, our results indicated that compared with wild-type mice, Selp ¡/¡ and Selplg ¡/¡ mice were more sensitive to LT. In addition, the recombinant sP-sel treatment markedly ameliorated LT-mediated pathogenesis and reduced mortality. As a result, elicitation of circulating sP-sel is potentially a self-rescue response, which is beneficial to host recovery from an LT-induced hypocoagulation state. These results suggest that the administration of sP-sel is likely to be useful in the development of a new strategy to treat anthrax. KEYWORDSanthrax lethal toxin; hemostasis; microparticle; Soluble P-selectin; P-selectin ligand 1

Thioacetamide-induced liver damage and thrombocytopenia is associated with induction of antiplatelet autoantibody in mice

“…Liver damage was analysed by measuring the amounts of hepatocyte-specific enzymes AST and ALT that were released into the plasma, which was performed using previously described methods 24–26 . In brief, a blood sample from a patient or experimental animal (rats and mice) was collected and mixed with anticoagulant citrate dextrose solution (ACD; 38 mM citric acid, 75 mM sodium citrate, and 100 mM dextrose) 27,28 in an Eppendorf tube. After centrifugation to remove the blood cells, the levels of plasma AST and ALT were then measured using a clinical biochemistry analysis system (COBAS INTEGRA 800, Roche Taiwan, Taipei, Taiwan) 24,25 over the appropriate time courses.…”

“…Experimental animals were maintained at a specific pathogen free condition with consistent temperature and humidity controls, and 12 h light/dark cycle 27,29,32,33 . Acute liver damage and thrombocytopenia were chemically induced using TAA in rat and mouse models by employing a method modified from those previously reported 34,35 .…”

TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice

“…C57BL/6J male mice (8–12 wk old), purchased from the National Laboratory Animal Center (Taipei, Taiwan), were used in experiments. C57BL/6J male mice (8–12 wk old) deficient in P-selectin (B6; 129S2- Selp tm1Hyn /J) [ 21 , 36 , 37 ], Ighm (BCD; B6.129S2- Ighm tm1Cgn /J), and TRPM8 (B6.129P2- Trpm8 tm1Jul /J) were purchased from the Jackson Laboratory (Maine, USA). All animals were maintained in an specific-pathogen-free (SPF) facility in the Laboratory Animal Center of Tzu Chi University (Hualien, Taiwan).…”

“…Mouse blood samples were collected from the retro-orbital venous plexus and mixed with an anticoagulant acid-citrate-dextrose solution (ACD; 38 mM citric acid, 75 mM sodium citrate, 100 mM dextrose) [ 21 , 36 , 37 ] in Eppendorf tubes. The plasma renin activity was measured using the Renin activity kit (Abcam, Cambridgeshire, UK).…”

Self-defense againstBacillus anthracistoxins: Is P-selectin the key?

“…13 sP-sel also has pro-coagulant effects through increasing numbers of circulating tissue factor expressing microparticles. 14 In the present work, 12 Sun and colleagues used a model of anthrax pathology in which mice intravenously injected with LT develop key features of anthrax pathology such as hemorrhage and thrombocytopenia. Interestingly, despite this evidence of LT-induced impairment of coagulation, LT administration also increased levels of sP-sel in mouse plasma and increased circulating microparticles, the latter effect absent in P-sel or PSGL-1 knockout mice.…”