title: Rapamycin blocks fibrocyte migration and attenuates bronchiolitis obliterans in a murine model.
abstract: BACKGROUND
  Fibrocytes are integral in the development of fibroproliferative disease. The CXCL12/CXCR4 chemokine axis has been shown to play a central role in fibrocyte migration and the development of bronchiolitis obliterans (BO) after lung transplantation. Inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin has been shown to decrease expression of both CXCR4 and its receptor agonist CXCL12. Thus, we hypothesized that rapamycin treatment would decrease fibrocyte trafficking into tracheal allografts and prevent BO.
  
  
  METHODS
  A total alloantigenic mismatch murine heterotopic tracheal transplant (HTT) model of BO was used. Animals were either treated with rapamycin or dimethyl sulfoxide (DMSO) for 14 days after tracheal transplantation. Fibrocyte levels were assessed by flow cytometry, and allograft neutrophil, CD3(+) T-cell, macrophage, and smooth muscle actin (SMA) levels were assessed by immunohistochemistry. Tracheal luminal obliteration was assessed on hematoxylin and eosin (H&E) stains.
  
  
  RESULTS
  Compared with DMSO-treated controls, rapamycin-treated mice showed a significant decrease in fibrocyte levels in tracheal allografts. Fibrocyte levels in recipient blood showed a similar pattern, although it was not statistically significant. Furthermore, animals treated with rapamycin showed a significant decrease in tracheal allograft luminal obliteration compared with controls. Based on immunohistochemical analyses, populations of α-SMA-positive (α-SMA(+)) cells, neutrophils, CD3(+) T cells, and macrophages were all decreased in rapamycin-treated allografts versus DMSO controls.
  
  
  CONCLUSIONS
  Rapamycin effectively reduces recruitment of fibrocytes into tracheal allografts and mitigates development of tracheal luminal fibrosis. Further studies are needed to determine the cellular and molecular mechanisms that mediate the protective effect of rapamycin against BO.
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA 22908-0679, USA.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Gillen
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Lapar
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Stone
authors.forename: Lucas G
authors.initials: LG
authors.lastname: Fernandez
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000502:physiology; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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