Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats

Julie Boisramé-Helms; Xavier Delabranche; Su-Emmanuelle Degirmenci; Fatiha Zobairi; Asael Berger; Grégory Meyer; Mélanie Burban; Hadj-Ahmed Mostefai; Bruno Levy; Florence Toti; Ferhat Meziani

doi:10.1160/TH13-04-0313

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(01): 154-164
DOI: 10.1160/TH13-04-0313

Animal Models

Schattauer GmbH

Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats

Julie Boisramé-Helms^*

¹Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

²EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France

,

Xavier Delabranche^*

¹Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

²EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France

,

Su-Emmanuelle Degirmenci

²EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France

,

Fatiha Zobairi

³EA 7293, Stress Vasculaire et Tissulaire en Transplantation, Faculté de Médecine, Université de Strasbourg, France

,

Asael Berger

¹Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

²EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France

,

Grégory Meyer

⁴Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France

,

Mélanie Burban

⁴Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France

,

Hadj-Ahmed Mostefai

¹Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

,

Bruno Levy

⁵Groupe CHOC, Equipe AVENIR Inserm, Faculté de Médecine, Université de Nancy, Vandoeuvre les Nancy, Nancy, France

,

Florence Toti

³EA 7293, Stress Vasculaire et Tissulaire en Transplantation, Faculté de Médecine, Université de Strasbourg, France

⁴Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France

,

Ferhat Meziani

¹Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

²EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France

› Author Affiliations

Abstract

Summary

Circulating microparticles play a pro-inflammatory and procoagulant detrimental role in the vascular dysfunction of septic shock. It was the objective of this study to investigate mechanisms by which a pharmacological modulation of microparticles could affect vascular dysfunction in a rat model of septic shock. Septic or sham rats were treated by activated protein C (aPC) and resuscitated during 4 hours. Their microparticles were harvested and inoculated to another set of healthy recipient rats. Haemodynamic parameters were monitored, circulating total procoagulant microparticles assessed by prothrombinase assay, and their cell origin characterised. Mesenteric resistance arteries, aorta and heart were harvested for western blotting analysis. We found that a) the amount and phenotype of circulating microparticles were altered in septic rats with an enhanced endothelial, leucocyte and platelet contribution; b) aPC treatment significantly reduced the generation of leucocyte microparticles and norepinephrine requirements to reach the mean arterial pressure target in septic rats; c) Microparticles from untreated septic rats, but not from aPC-treated ones, significantly reduced the healthy recipients’ mean arterial pressure; d) Microparticle thromboxane content and aPC activity were significantly increased in aPC-treated septic rats. In inoculated naïve recipients, microparticles from aPC-treated septic rats prompted reduced NF-κB and cyclooxygenase-2 arterial activation, blunted the generation of pro-inflammatory iNOS and secondarily increased platelet and endothelial microparticles. In conclusion, in this septic shock model, increased circulating levels of procoagulant microparticles led to negative haemodynamic outcomes. Pharmacological treatment by aPC modified the cell origin and levels of circulating microparticles, thereby limiting vascular inflammation and favouring haemodynamic improvement.

Keywords

Activated protein C - haemodynamic dysfunction - inflammation - microparticles - septic shock

Full Text

References

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