title: Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice.
abstract: Evidence is emerging that platelets are major contributors to innate immune responses in conditions such as acute lung injury (ALI). Platelets form heterotypic aggregates with neutrophils, and we hypothesized that lipoxin mediators regulate formation of neutrophil-platelet aggregates (NPA) and that NPA significantly contribute to ALI. Lipopolysaccharide (LPS)-induced lung injury was accompanied by platelet sequestration, activation, intra-alveolar accumulation, and NPA formation within both blood and alveolar compartments. Using lung intravital microscopy, we observed the dynamic formation of NPA during physiologic conditions, which sharply increased with ALI. Aspirin (ASA) treatment significantly reduced lung platelet sequestration and activation, NPA formation, and lung injury. ASA treatment increased levels of ASA-triggered lipoxin (ATL; 15-epi-lipoxin A4), and blocking the lipoxin A4 receptor (ALX) with a peptide antagonist (Boc2) or using ALX knockouts (Fpr2/3(-/-)) reversed this protection. LPS increased NPA formation in vitro, which was reduced by ATL, and engagement of ALX by ATL on both neutrophils and platelets was necessary to prevent aggregation. In a model of transfusion-related acute lung injury (TRALI), Boc2 also reversed ASA protection, and treatment with ATL in both LPS and TRALI models protected from ALI. We conclude that ATL regulates neutrophil-platelet aggregation and that platelet-neutrophil interactions are a therapeutic target in lung injury.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA;
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA;
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands;
authors.forename: Adriaan
authors.initials: A
authors.lastname: Bins
authors.affiliation: Department of Pathology and.
authors.forename: Mark
authors.initials: M
authors.lastname: Headley
authors.affiliation: Department of Pathology and.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002450:Cell Communication / Q000187:drug effects; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000097:blood / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D065227:Transfusion Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D044045:Lipoxins; D008164:Luminescent Proteins; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D001241:Aspirin