title: Neutrophil mediated smooth muscle cell loss precedes allograft vasculopathy.
abstract: BACKGROUND
  Cardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC), the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR) injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts.
  
  
  METHODS
  Aortic transplants were performed between fully disparate mouse strains (C3H/HeJ and C57BL/6), in the presence of therapeutic levels of Cyclosporine A, as a model for cardiac AV. Neutrophils were depleted from some recipients using anti-PMN serum. Grafts were harvested at 1,2,3,5d and 1,2wk post-transplant. Ultrastructural integrity was examined by transmission electron microscopy. SMC and neutrophils were quantified from histological sections in a blinded manner.
  
  
  RESULTS
  Grafts exposed to cold ischemia, but not transplanted, showed no medial SMC loss and normal ultrastructural integrity. In comparison, allografts harvested 1d post-transplant exhibited > 90% loss of SMC (p < 0.0001). SMC partially recovered by 5d but a second loss of SMC was observed at 1wk. SMC loss at 1d and 1wk post-transplant correlated with neutrophil influx. SMC loss was significantly reduced in neutrophil depleted recipients (p < 0.01).
  
  
  CONCLUSIONS
  These novel data show that there is extensive damage to medial SMC at 1d post-transplant. By depleting neutrophils from recipients it was demonstrated that a portion of the SMC loss was mediated by neutrophils. These results provide evidence that IR activation of early innate events contributes to the etiology of AV.
authors.affiliation: Department of Pathology, 5850 College St, Dalhousie University, Halifax, NS, Canada.
authors.forename: Chelsey L
authors.initials: CL
authors.lastname: King
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Devitt
authors.forename: Timothy D G
authors.initials: TD
authors.lastname: Lee
authors.forename: Camille L
authors.initials: CL
authors.lastname: Hancock Friesen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009504:Neutrophils / Q000276:immunology*; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000276:immunology*