JCJC SVSE 1 - JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique

Platelet-associated Inflammation in Severe Sepsis – PlatISSep

Submission summary


Sepsis represents a serious public health issue characterized by a complex inflammatory response. This project emphasises on the proinflammatory role of platelets during sepsis. We postulate that, in severe sepsis, platelets become activated and release amounts of different soluble inflammatory molecules that contribute to sepsis-associated inflammation. In turn, the use of molecules limiting platelet activation is hoped to reduce the participation of platelets in maintenance of the acute inflammatory response observed in sepsis; this would open new perspectives in handling patients with severe sepsis. To address this question, we propose an innovative approach combining ex vivo and in vivo investigations, together with an in vitro modelling of platelet involvement in sepsis. We propose to evaluate the anti-inflammatory effects of several anti-platelet molecules through the inhibition of pro-inflammatory factor release by platelets.
It is noticeable that, in addition to historical anti-platelet agents (aspirin, ticlopidine, clopidogrel or abciximab) several drugs have been shown to decrease the release of platelet microparticles including pravastatin, eprosartan and nifedipine. Further, our works led us to demonstrate the importance of cell-signalling molecules and their activation in platelets, despite those cells are anucleate: protein kinases or NF-kB for instance, seem to underly promising therapeutic strategies for inflammation-linked pathology.
Therefore, to study platelet involvement in inflammation during sepsis and to evaluate the ability of anti-platelet molecules and cell-signalling inhibitors to reduce platelet-related inflammation, three different pathways will be explored. First, we will examine, ex vivo, the activation state and the inflammatory functions (release of inflammatory molecules and soluble TLRs and modulation their signalosome) of platelets from patients with severe sepsis in response to stimulation by thrombin and TLR-ligand. The ability of sepsis platelets to activate normal monocytes and neutrophils will also be evaluated. Second, we will focus on the direct interactions of healthy donors’ platelets with S. aureus, a common sepsis inducer, using the whole bacterium or its exotoxins, and their effects on the parameters described just before. The third approach will use murine models of sepsis and endotoxemia to study in vivo platelet pro-inflammatory response and the signalosome. In addition, these three approaches will allow estimating the capacity of anti-platelet molecules and cell-signalling inhibitors to reduce platelet inflammatory response during sepsis.
The program strength relies on the complementary nature of the research domains from different partners, both from University Hospital and Academic laboratories, who have already made significant contributions to the fields of platelet inflammatory functions, signalosome investigation, molecular and cellular characterization of bacterial infection and virulence factors, and foremost clinical data analysis.
This program is expected to lead to new diagnostic tests as well as novel critical care protocols. Standardized methodologies and tools will be developed and could become international references for sepsis management. Moreover, identification of platelet-related molecules involved in sepsis-associated inflammation may lead, in view of its extension to a larger program, to the definition of new sepsis biomarkers. We next expect to attract industrial partners through the Lyonbiopôle consortium (one of the six internationally competitive clusters accredited by the French State) to which this project is affiliated. To conclude, these three workpackages, will put forward the evidence of the crucial role of platelets in severe sepsis, leading to identify new inflammation biomarkers and to propose insights to new therapeutic strategies in targeting platelet functions.

Project coordination

Fabrice COGNASSE (Groupe Immunité des Muqueuses et Agents Pathogènes EA 3064) – fabrice.cognasse@univ-st-etienne.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

GIMAP EA 3064 Groupe Immunité des Muqueuses et Agents Pathogènes EA 3064

Help of the ANR 250,000 euros
Beginning and duration of the scientific project: February 2013 - 36 Months

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