title: Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model.
abstract: OBJECTIVE
  Fibrocytes are integral in the development of fibroproliferative disease after lung transplantation. Undifferentiated fibrocytes (CD45+anti-collagen 1+CXCR4+) preferentially traffic by way of the CXCR4/CXCL12 axis and differentiate into smooth muscle actin-producing (CD45+CXCR4+α-smooth muscle actin+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts.
  
  
  METHODS
  A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. The mice were treated with either goat-anti-human CXCL12 F(ab')(2) or goat IgG F(ab')(2). Buffy coat, bone marrow, and trachea allografts were collected and analyzed using flow cytometry. Tracheal luminal obliteration was assessed using hematoxylin-eosin and Direct Red 80 collagen stain.
  
  
  RESULTS
  Compared with the controls, the anti-CXCL12-treated mice showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days after transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In the anti-CXCL12-treated mice, there was a 35% decrease in luminal obliteration at 21 days (65% vs 100% obliterated; interquartile range, 38% vs 10%; P = .010) and decreased luminal collagen deposition at 21 and 28 days after transplantation (P = .042 and P = .012, respectively).
  
  
  CONCLUSIONS
  Understanding the role of fibrocytes in airway fibrosis after lung transplantation could lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced the deterioration of the tracheal allografts. Thus, the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration after lung transplantation, and the quantification of fibrocyte populations could provide clinicians with a biomarker of fibrosis, allowing individualized drug therapy.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908-0679, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.forename: Abbas
authors.initials: A
authors.lastname: Emaminia
authors.forename: John F
authors.initials: JF
authors.lastname: Steidle
authors.forename: Mark
authors.initials: M
authors.lastname: Stoler
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
mesh_terms: D000818:Animals; D058621:Blood Buffy Coat / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000601:surgery*; D002454:Cell Differentiation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology*; D005355:Fibrosis; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D019718:Receptors, CXCR4 / Q000276:immunology*; D013194:Staining and Labeling; D018709:Statistics, Nonparametric; D014132:Trachea / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4