title: Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome.
abstract: Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2(-/-) mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90024-1922, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Belperio
authors.forename: M P
authors.initials: MP
authors.lastname: Keane
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: J P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Y Y
authors.initials: YY
authors.lastname: Xue
authors.forename: A
authors.initials: A
authors.lastname: Berlin
authors.forename: D J
authors.initials: DJ
authors.lastname: Ross
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: I F
authors.initials: IF
authors.lastname: Charo
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000378:metabolism; D016041:Heart-Lung Transplantation; D006801:Humans; D016130:Immunophenotyping; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D010587:Phagocytosis; D011183:Postoperative Complications / Q000209:etiology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
chemical_list: C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine