PB1375 - Impact of ticagrelor pretreatment in a cecal slurry mouse model of polymicrobial abdominal sepsis

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

AM

Alexandre Mansour

MD-PhD
Department of Anesthesia and Critical Care, Pontchaillou University Hospital, IRSET-INSERM-1085, Univ Rennes, France
Rennes, Bretagne, France
Isabelle Gouin Thibault

PhD - PharmD
Laboratoire d'Hématology, Pontchaillou University Hospital of Rennes, IRSET-INSERM-1085, Univ Rennes, France.
Rennes, Bretagne, France
ER

Elisa Rossi

Researcher
INSERM U1140, Université Paris Cité, Paris, France
Paris, Ile-de-France, France
AM

Aurore Marchelli

M.Sc
Université Paris Cité, Inserm UMR-S 1140
Paris, Ile-de-France, France
TB

Tiphaine Belleville

Pharm.D., Ph.D.
Université Paris Cité, Inserm UMR-S 1140
Paris, Ile-de-France, France
NN

Nicolas Nesseler

M.D., Ph.D.
Department of Anesthesia and Critical Care, Pontchaillou, University Hospital of Rennes, France. Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d’Investigation Clinique de Rennes), F35000 Rennes, France. Univ Rennes, CHU de Rennes, Inra, Inserm, Institut NUMECAN – UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
Rennes, Bretagne, France
PG

Pascale Gaussem

PharmD, PhD
Université Paris Cité, Inserm UMR-S1140, Hôpital Européen Georges Pompidou
Paris, Ile-de-France, France

Presenting Author(s)

CB

Christilla Bachelot-Loza, PhD

PhD
Université Paris Cité, Inserm UMR-S 1140
Paris, Ile-de-France, France

Background: During sepsis, organ failure results from a complex interplay between innate immunity, coagulation, endothelium and platelet activation. Studies have suggested a potential beneficial effect of P2Y12 inhibition during sepsis, although with conflicting results. Ticagrelor, an oral direct-acting P2Y12 inhibitor, has demonstrated a more potent and consistent platelet inhibitory effect in clinical cardiovascular studies and in murine sepsis model.

Aims: The study aimed to evaluate the effect of ticagrelor on inflammatory response and organ injuries in a murine model of severe polymicrobial abdominal sepsis.

Methods: In this experiment, polymicrobial sepsis was induced by intraperitoneal injection of cold-stored cecal slurry (Cecal Slurry model, Figure 1). Male C57BL/6JRj mice were treated with either ticagrelor (100 mg/kg) or a placebo (10mM HCl) by oral gavage 1 hour before the intraperitoneal injection of cecal slurry. Key assessments included blood cell counts, inflammatory markers and lung histology.

Results: Cecal slurry model induced a severe sepsis phenotype with hypothermia, high murine sepsis score, thrombocytopenia, leucopenia, increased inflammatory markers, and acute lung injury (Figure 2). In ticagrelor-treated mice (Figure 2), hypothermia and sepsis score were improved, thrombocytopenia (637 (534-771) G/L vs 501(398-621) G/L, p=0.007) and leucopenia ( 3.1 (2.3-4.6) G/L vs 2.1 (1.7-3.0) G/L, p=0.028) were less pronounced. Ticagrelor pre-treatment was associated with a reduction of both TNF-α and IL-6 levels (Figure 2). Histological analysis indicated a significant decrease in acute lung injury in the ticagrelor group, with a median lung injury score of 0.47 (0.35-0.58) compared to 0.66 (0.56-0.73) in the placebo group (p=0.026).

Conclusion(s): The murine cecal slurry model of polymicrobial sepsis serves as an effective platform for evaluating the impact of pharmaceutical interventions. Pre-treatment with ticagrelor prior to sepsis induction was associated with reduced inflammatory response and acute lung injury. These results warrant additional investigation into ticagrelor’s role in sepsis management, focusing on its underlying mechanisms