P2Y12 Receptor Modulates Sepsis-Induced Inflammation

Objective-Platelets modulate hemostasis and immune responses via interactions with immune cells through secretion of immunemodulators and cell-cell interactions. The P2Y(12) receptor mediates ADP-induced aggregation and secretion in platelets. Approach and Results-Using a mouse model of intra-abdominal sepsis and acute lung injury, we investigated the role of the P2Y(12) receptor in neutrophil migration and lung inflammation in P2Y(12) null mice and in mice pretreated with the P2Y(12) antagonist clopidogrel. Our data show a decrease in circulating white blood cells and a decrease in platelet activation and platelet-leukocyte interactions in treated mice compared with untreated mice. Additionally, lung injury and platelet sequestration were diminished in clopidogrel-treated mice compared with their untreated septic littermates. Similar results were observed in P2Y(12) null mice: platelet activation and platelet-leukocyte aggregates were decreased in septic P2Y(12) null mice compared with wild-type mice. P2Y(12) null mice were refractory to lung injury compared with wild-type mice. Finally, to evaluate P2Y(12)-independent effects of clopidogrel, we pretreated P2Y(12) null mice. Interestingly, the number of circulating neutrophils was reduced in treated septic P2Y(12) null mice, suggesting neutrophils as a target for clopidogrel pleiotropic effects. No difference was observed in P2Y(1) null mice during sepsis, indicating that the P2Y(12) receptor is responsible for the effects. Conclusions-P2Y(12) null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y(12) receptor during sepsis.