Platelet P2Y12 Receptor Deletion or Pharmacological Inhibition does not Protect Mice from Sepsis or Septic Shock

Author:

Rabouel Yannick1,Magnenat Stéphanie1,Delabranche Xavier2,Gachet Christian1,Hechler Beatrice1

Affiliation:

1. Université de Strasbourg, INSERM, Etablissement Français du Sang (EFS)-Grand Est, BPPS UMR_S 1255, Fédération de Médecine Translationnelle de Strasbourg (FMTS), F-67000 Strasbourg, France

2. Hôpitaux Universitaires de Strasbourg, Anesthésie, Réanimation et Médecine périopératoire, Nouvel Hôpital Civil, F-67000 Strasbourg, France

Abstract

Abstract Introduction Platelets are increasingly appreciated as key effectors during sepsis, raising the question of the usefulness of antiplatelet drugs to treat patients with sepsis. Objective Evaluate the potential contribution of the platelet P2Y12 receptor in the pathogenesis of polymicrobial-induced sepsis and septic shock in mice. Methods The effects of P2Y12 inhibition using clopidogrel treatment and of platelet-specific deletion of the P2Y12 receptor in mice were examined in two severity grades of cecal ligation and puncture (CLP) leading to mild sepsis or septic shock. Results Twenty hours after induction of the high grade CLP, clopidogrel- and vehicle-treated mice displayed a similar 30% decrease in mean arterial blood pressure (MAP) characteristic of shock. Septic shock-induced thrombocytopenia was not modified by clopidogrel treatment. Plasma concentrations of inflammatory cytokines and myeloperoxidase (MPO) were similarly increased in clopidogrel- and vehicle-treated mice, indicating comparable increase in systemic inflammation. Thrombin-antithrombin (TAT) complexes and the extent of organ damage were also similar. In mild-grade CLP, clopidogrel- and vehicle-treated mice did not display a significant decrease in MAP, while thrombocytopenia and plasma concentrations of TNFα, IL6, IL10, MPO, TAT and organ damage reached similar levels in both groups, although lower than those reached in the high grade CLP. Similarly, mice with platelet-specific deletion of the P2Y12 receptor were not protected from CLP-induced sepsis or septic shock. Conclusion The platelet P2Y12 receptor does not contribute to the pathogenesis of sepsis or septic shock in mice, suggesting that P2Y12 receptor antagonists may not be beneficial in patients with sepsis or septic shock.

Funder

ARMESA (Association de Recherche et Développement en Médecine et Santé Publique

Etablissement Français du Sang

Institut National de la Santé et de la Recherche Médicale

Publisher

Georg Thieme Verlag KG

Reference51 articles.

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