title: Experimental design of complement component 5a-induced acute lung injury (C5a-ALI): a role of CC-chemokine receptor type 5 during immune activation by anaphylatoxin.
abstract: Excessive activation of the complement system is detrimental in acute inflammatory disorders. In this study, we analyzed the role of complement-derived anaphylatoxins in the pathogenesis of experimental acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in C57BL/6J mice. Intratracheal administration of recombinant mouse complement component (C5a) caused alveolar inflammation with abundant recruitment of Ly6-G(+)CD11b(+) leukocytes to the alveolar spaces and severe alveolar-capillary barrier dysfunction (C5a-ALI; EC(50[C5a]) = 20 ng/g body weight). Equimolar concentrations of C3a or desarginated C5a (C5a(desArg)) did not induce alveolar inflammation. The severity of C5a-ALI was aggravated in C5-deficient mice. Depletion of Ly6-G(+) cells and use of C5aR1(-/-) bone marrow chimeras suggested an essential role of C5aR1(+) hematopoietic cells in C5a-ALI. Blockade of PI3K/Akt and MEK1/2 kinase pathways completely abrogated lung injury. The mechanistic description is that C5a altered the alveolar cytokine milieu and caused significant release of CC-chemokines. Mice with genetic deficiency of CC-chemokine receptor (CCR) type 5, the common receptor of chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5, displayed reduced lung damage. Moreover, treatment with a CCR5 antagonist, maraviroc, was protective against C5a-ALI. In summary, our results suggest that the detrimental effects of C5a in this model are partly mediated through CCR5 activation downstream of C5aR1, which may be evaluated for potential therapeutic exploitation in ALI/ARDS.
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Norman F
authors.initials: NF
authors.lastname: Russkamp
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ruemmler
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Roewe
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.affiliation: *Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA markus.bosmann@unimedizin-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology; D003167:Complement Activation; D015926:Complement C3a / Q000235:genetics / Q000378:metabolism*; D015937:Complement C5a, des-Arginine / Q000235:genetics / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D000077592:Maraviroc; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C000591759:C5ar1 protein, mouse; D065100:CCR5 Receptor Antagonists; C000592874:CCR5 protein, mouse; D015937:Complement C5a, des-Arginine; D003510:Cyclohexanes; D044087:Receptor, Anaphylatoxin C5a; D019713:Receptors, CCR5; D014230:Triazoles; D015926:Complement C3a; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D000077592:Maraviroc
keywords: ARDS; C5aR1; cytokines; maraviroc; polymorphonuclear neutrophils