[en] ATP-gated P2X1 ion channels contribute to arterial thrombosis by amplifying platelet activation. In the search for novel anti-platelet strategies, targeting P2X1 ion channels is appealing. However, in this study we found that lack or inhibition of P2X1 channels enhanced neutrophil respiratory burst activity ex vivo.
<br />To study the consequence of P2X1 deficiency on neutrophil function in vivo, P2X1-/- mice were used in a model of endotoxin-induced sepsis. Upon injection of lipopolysaccharides (LPS), plasma myeloperoxidase (MPO) concentrations reached higher levels in the P2X1-/- mice, and circulating neutrophils expressed higher levels of surface CD11b compared to wild-type mice. Neutrophil relocalization into the lungs of LPS-treated P2X1-/- mice was also significantly augmented, reflecting a higher activation state of P2X1-/- neutrophils under conditions of sepsis. Accordingly, more extensive lipid peroxidation was observed in the liver of LPS-treated P2X1-/- mice, indicative of exaggerated oxidative damage. Concomitantly, the levels of thrombin-antithrombin complexes were higher in the plasma of LPS-treated P2X1-/- mice and thrombocytopenia was worsened as compared to wild type mice. Elevated numbers of microthrombi were also found in the lungs of these mice. These observations coincided with a higher susceptibility of P2X1-/- mice to LPS-induced septic shock than wild type animals.
<br />Our results strongly suggest that P2X1 ion channels play a protective role in sepsis by negatively regulating systemic neutrophil activation, thereby limiting oxidative damage, activation of coagulation and platelet accumulation into the lungs. Therefore, since antagonists of P2X1 ion channels may not only target platelets but also affect neutrophils, inhibiting these channels in the highly inflammatory environment of severe sepsis or of acute coronary syndromes might be detrimental.
Disciplines :
Hematology
Author, co-author :
Lecut, Christelle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine