Elisabetta Liverani1, Mario C Rico2, Alexander Y Tsygankov2, Laurie E Kilpatrick2, Satya P Kunapuli2. 1. 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. 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: P2Y12 null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y12 receptor during sepsis.
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS:P2Y12 null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y12 receptor during sepsis.
Authors: Stephen R Clark; Adrienne C Ma; Samantha A Tavener; Braedon McDonald; Zahra Goodarzi; Margaret M Kelly; Kamala D Patel; Subhadeep Chakrabarti; Erin McAvoy; Gary D Sinclair; Elizabeth M Keys; Emma Allen-Vercoe; Rebekah Devinney; Christopher J Doig; Francis H Y Green; Paul Kubes Journal: Nat Med Date: 2007-03-25 Impact factor: 53.440
Authors: Guoying Zhang; Jingyan Han; Emily J Welch; Richard D Ye; Tatyana A Voyno-Yasenetskaya; Asrar B Malik; Xiaoping Du; Zhenyu Li Journal: J Immunol Date: 2009-06-15 Impact factor: 5.422
Authors: Harald F Langer; Karin Daub; Gregor Braun; Tanja Schönberger; Andreas E May; Martin Schaller; Gerburg M Stein; Konstantinos Stellos; Andreas Bueltmann; Dorothea Siegel-Axel; Hans P Wendel; Hermann Aebert; Martin Roecken; Peter Seizer; Sentot Santoso; Sebastian Wesselborg; Peter Brossart; Meinrad Gawaz Journal: Arterioscler Thromb Vasc Biol Date: 2007-03-22 Impact factor: 8.311
Authors: Muhammad Asaduzzaman; Shahram Lavasani; Milladur Rahman; Su Zhang; Oscar O Braun; Bengt Jeppsson; Henrik Thorlacius Journal: Crit Care Med Date: 2009-04 Impact factor: 7.598
Authors: Thiago Inácio Teixeira do Carmo; Victor Emanuel Miranda Soares; Jonatha Wruck; Fernanda Dos Anjos; Débora Tavares de Resende E Silva; Sarah Franco Vieira de Oliveira Maciel; Margarete Dulce Bagatini Journal: Inflamm Res Date: 2021-04-27 Impact factor: 4.575
Authors: Theodora A M Claushuis; Alex F de Vos; Joris J T H Roelofs; Onno J de Boer; Cornelis van 't Veer; Tom van der Poll Journal: J Innate Immun Date: 2018-12-17 Impact factor: 7.349
Authors: Harika Vemulapalli; Samara Albayati; Viren C Patwa; Douglas G Tilley; Alexander Y Tsygankov; Elisabetta Liverani Journal: J Cell Commun Signal Date: 2019-12-05 Impact factor: 5.782
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311