title: Platelet-Specific Chemokines Contribute to the Pathogenesis of Acute Lung Injury.
abstract: Platelets and neutrophils contribute to the development of acute lung injury (ALI). However, the mechanism by which platelets make this contribution is incompletely understood. We investigated whether the two most abundant platelet chemokines, CXCL7, which induces neutrophil chemotaxis and activation, and CXCL4, which does neither, mediate ALI through complementary pathogenic pathways. To examine the role of platelet-derived chemokines in the pathogenesis of ALI using Cxcl7-/-and Cxcl4-/-knockout mice and mice that express human CXCL7 or CXCL4, we measured levels of chemokines in these mice. ALI was then induced by acid aspiration, and the severity of injury was evaluated by histology and by the presence of neutrophils and protein in the bronchoalveolar lavage fluid. Pulmonary vascular permeability was studied in vivo by measuring extravasation of fluorescently labeled dextran. Murine CXCL7, both recombinant and native protein released from platelets, can be N-terminally processed by cathepsin G to yield a biologically active CXCL7 fragment. Although Cxcl7-/-mice are protected from lung injury through the preservation of endothelial/epithelial barrier function combined with impaired neutrophils transmigration, Cxcl4-/-mice are protected through improved barrier function without affecting neutrophils transmigration to the airways. Sensitivity to ALI is restored by transgenic expression of CXCL7 or CXCL4. Platelet-derived CXCL7 and CXCL4 contribute to the pathogenesis of ALI through complementary effects on neutrophil chemotaxis and through activation and vascular permeability.
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.affiliation: Divisions of 2 Hematology and.
authors.forename: Kandace
authors.initials: K
authors.lastname: Gollomp
authors.affiliation: 3 Department of Cytobiology and Proteomics, Medical University of Lodz, Lodz, Poland; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Stasiak
authors.affiliation: 4 Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Junjie
authors.initials: J
authors.lastname: Mei
authors.affiliation: 5 Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Papiewska-Pajak
authors.affiliation: Divisions of 2 Hematology and.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.affiliation: 6 Pediatrics, University of Pennsylvania-Perelman School of Medicine, Philadelphia, Pennsylvania.|4 Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.affiliation: 6 Pediatrics, University of Pennsylvania-Perelman School of Medicine, Philadelphia, Pennsylvania.|Divisions of 2 Hematology and.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Divisions of 2 Hematology and.|5 Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: M Anna
authors.initials: MA
authors.lastname: Kowalska
mesh_terms: D055371:Acute Lung Injury / Q000097:blood*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002199:Capillary Permeability; D019743:Chemokines, CXC / Q000097:blood*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008822:Mice, Transgenic; D010978:Platelet Factor 4 / Q000097:blood*
chemical_list: D019743:Chemokines, CXC; C446301:Cxcl7 protein, mouse; D010978:Platelet Factor 4
keywords: acute lung injury; chemokines; platelets