title: P2Y12 Receptor Modulates Sepsis-Induced Inflammation.
abstract: 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.
authors.affiliation: From the Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.Y.T., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), Department of Microbiology and Immunology (A.Y.T.), and Center for Inflammation, Translational and Clinical Lung Research (E.L., L.E.K.), Temple University School of Medicine, Philadelphia, PA. eliliverani@temple.edu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Liverani
authors.affiliation: From the Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.Y.T., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), Department of Microbiology and Immunology (A.Y.T.), and Center for Inflammation, Translational and Clinical Lung Research (E.L., L.E.K.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Mario C
authors.initials: MC
authors.lastname: Rico
authors.affiliation: From the Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.Y.T., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), Department of Microbiology and Immunology (A.Y.T.), and Center for Inflammation, Translational and Clinical Lung Research (E.L., L.E.K.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
authors.affiliation: From the Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.Y.T., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), Department of Microbiology and Immunology (A.Y.T.), and Center for Inflammation, Translational and Clinical Lung Research (E.L., L.E.K.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Kilpatrick
authors.affiliation: From the Sol Sherry Thrombosis Research Center (E.L., M.C.R., A.Y.T., L.E.K., S.P.K.), Department of Physiology (L.E.K., S.P.K.), Department of Microbiology and Immunology (A.Y.T.), and Center for Inflammation, Translational and Clinical Lung Research (E.L., L.E.K.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000077144:Clopidogrel; D016207:Cytokines / Q000097:blood; D020022:Genetic Predisposition to Disease; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D019007:P-Selectin / Q000097:blood; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016207:Cytokines; D019007:P-Selectin; C548577:P2ry12 protein, mouse; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: P2Y12 receptor; acute lung injury; neutrophils; platelets; sepsis