ORBi: Lecut Christelle - ATP-gated P2X1 ion channels protect from endotoxemia by dampening neutrophil activation

Reference : ATP-gated P2X1 ion channels protect from endotoxemia by dampening neutrophil activation


	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Hematology Life sciences : Genetics & genetic processes
	To cite this reference:	http://hdl.handle.net/2268/110157

Title :	ATP-gated P2X1 ion channels protect from endotoxemia by dampening neutrophil activation
Language :	English
Author, co-author :	Lecut, Christelle [Université de Liège - ULg > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine]
	Faccinetto, Céline [Université de Liège - ULg > > > Doct. sc. bioméd. & pharma. (Bologne)]
	Delierneux, Céline [Université de Liège - ULg > > > GIGA - Utilisateurs machines]
	van Oerle, Rene [University of Maastricht-CARIM > Internal Medicine > Laboratory for Clinical Thrombosis and Hemostasis > >]
	Spronk, Henri [University of Maastricht-CARIM > Internal Medicine > Laboratory for Clinical Thrombosis and Hemostasis > >]
	Evans, Richard J [University of Leicester > > > >]
	El Benna, Jamel [Université Paris Diderot - Paris 7 > > Centre de Recherche Biomédicale Bichat Beaujon CRB3 > >]
	Bours, Vincent [Université de Liège - ULg > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine]
	Oury, Cécile [Université de Liège - ULg > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine >]
Publication date :	2012
Journal title :	Journal of Thrombosis and Haemostasis [=JTH]
Publisher :	Blackwell Publishing
Volume :	10
Issue/season :	3
Pages :	453-65
Audience :	International
ISSN :	1538-7933
e-ISSN :	1538-7836
City :	Oxford
Country :	United Kingdom
Keywords :	[en] Sepsis ; P2 receptors ; mouse models
Abstract :	[en] Background: In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP-gated P2X1 ion channels are involved in promoting neutrophil chemotaxis. <br />Objectives: To elucidate the contribution of P2X1 ion channels to sepsis and associated disturbance of hemostasis. <br />Methods: We used P2X1-/- mice in a model of lipopolysaccharide (LPS)-induced sepsis. Hemostasis and inflammation parameters were analysed together with outcome. Mechanisms were further studied ex vivo using mouse and human blood or isolated neutrophils and monocytes. <br />Results: P2X1-/- mice were more susceptible to LPS-induced shock than wild-type mice despite normal cytokine production. Plasma levels of thrombin-antithrombin complexes were higher, thrombocytopenia was worsened and whole blood coagulation time was markedly reduced, pointing to aggravated hemostasis disturbance in the absence of P2X1. However, whole blood platelet aggregation occurred normally and P2X1-/- macrophages displayed normal levels of total tissue factor activity. We found that P2X1-/- neutrophils produced higher amounts of reactive oxygen species. Increased amounts of myeloperoxidase were released in the blood of LPS-treated P2X1-/- mice, and circulating neutrophils and monocytes expressed higher levels of CD11b. Neutrophil accumulation into the lungs was also significantly augmented, as was lipid peroxidation in the liver. Desensitization of P2X1 ion channels led to increased activation of human neutrophils and enhanced formation of platelet-leukocyte aggregates.
Permalink :	http://hdl.handle.net/2268/110157

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