title: Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse.
abstract: Obliterative bronchiolitis after lung transplantation is characterized by chronic airway inflammation leading to the obliteration of small airways. Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular responses to hypoxia and inflammation. The Von Hippel-Lindau protein (pVHL) drives the degradation of oxygen-sensitive subunit HIF-1α that controls the activity of HIF-1. We investigated the effect of myeloid cell-targeted gene deletion of HIF-1α or its negative regulator pVHL on the development of obliterative airway disease (OAD) in the recipients of tracheal allografts, a mouse model for obliterative bronchiolitis after lung transplantation.
  
  
  
  Tracheal allografts were heterotopically transplanted from BALB/c donor mice to fully major histocompatibility complex-mismatched recipient mice with HIF-1α or VHL gene deletion in myeloid cells. The recipients were left non-immunosuppressed or received tacrolimus daily. Histologic, immunohistochemical, and real-time reverse transcription polymerase chain reaction analyses were performed at 3, 10, and 30 days.
  
  
  
  In the absence of immunosuppression, myeloid cell-specific VHL deficiency of the recipient mice improved epithelial recovery, decreased inflammatory cell infiltration and expression of pro-inflammatory cytokines, increased regulatory forkhead box P3 messenger RNA expression, and reduced OAD development in tracheal allografts. In the presence of tacrolimus immunosuppression, loss of HIF-1α activity in myeloid cells of the recipient by HIF-1α gene deletion accelerated OAD development in mouse tracheal allografts.
  
  
  
  Activity of the HIF-pathway affects the development of allograft rejection, and our results suggest that myeloid cell-specific VHL-deficiency that potentially increases HIF-activity decreases allograft inflammation and the subsequent development of OAD in mouse tracheal allografts.
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland; Cardiac Surgery, Heart and Lung Center, Central Hospital, Helsinki University, Helsinki, Finland. Electronic address: jussi.o.ropponen@helsinki.fi.
authors: Jussi O
authors: JO
authors: Ropponen
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland.
authors: Mikko A
authors: MA
authors: Keränen
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland.
authors: Alireza
authors: A
authors: Raissadati
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland; Cardiac Surgery, Heart and Lung Center, Central Hospital, Helsinki University, Helsinki, Finland.
authors: Antti I
authors: AI
authors: Nykänen
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland.
authors: Rainer
authors: R
authors: Krebs
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland; Cardiac Surgery, Heart and Lung Center, Central Hospital, Helsinki University, Helsinki, Finland.
authors: Karl B
authors: KB
authors: Lemström
authors: Transplantation Laboratory, Helsinki University, Helsinki, Finland; Cardiac Surgery, Heart and Lung Center, Central Hospital, Helsinki University, Helsinki, Finland.
authors: Jussi M
authors: JM
authors: Tikkanen
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans; D015687:Cell Hypoxia; D006084:Graft Rejection; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016040:Lung Transplantation; D051379:Mice; D014184:Transplantation, Homologous
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Von Hippel-Lindau protein; allograft rejection; hypoxia-inducible factor-1; lung transplantation; obliterative bronchiolitis