Platelets modulate hemostasis and immune responses via interactions with immune cells through secretion of immunemodulators and cell–cell interactions. The P2Y₁₂ receptor mediates ADP-induced aggregation and secretion in platelets.

Using a mouse model of intra-abdominal sepsis and acute lung injury, we investigated the role of the P2Y₁₂ receptor in neutrophil migration and lung inflammation in P2Y₁₂ null mice and in mice pretreated with the P2Y₁₂ 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 P2Y₁₂ null mice: platelet activation and platelet–leukocyte aggregates were decreased in septic P2Y₁₂ null mice compared with wild-type mice. P2Y₁₂ null mice were refractory to lung injury compared with wild-type mice. Finally, to evaluate P2Y₁₂-independent effects of clopidogrel, we pretreated P2Y₁₂ null mice. Interestingly, the number of circulating neutrophils was reduced in treated septic P2Y₁₂ null mice, suggesting neutrophils as a target for clopidogrel pleiotropic effects. No difference was observed in P2Y₁ null mice during sepsis, indicating that the P2Y₁₂ receptor is responsible for the effects.

P2Y₁₂ null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y₁₂ receptor during sepsis.