title: Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis.
abstract: Abstract Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet-neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.
authors.affiliation: Department of Surgery, Lund University , Malmö , Sweden .
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
authors.forename: Oscar Ö
authors.initials: OÖ
authors.lastname: Braun
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010974:Platelet Aggregation / Q000187:drug effects; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D018805:Sepsis / Q000150:complications / Q000209:etiology / Q000378:metabolism*; D000077486:Ticagrelor
chemical_list: D019743:Chemokines, CXC; D016177:Macrophage-1 Antigen; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine