title: Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model.
abstract: Obliterative bronchiolitis (OB) is the major limiting factor for long-term survival after lung transplantation. As previously shown, donor treatment with a PHD-inhibitor activating hypoxia-inducible transcription factors (HIFs) prevents graft injury both in an allogenic kidney and aortic allograft transplant model. The aim of this study was to investigate the effect of HIF activation with a PHD-inhibitor on the development of OB.
  
  
  
  Fully MHC-mismatched C57BL/6 (H-2b) donor tracheas were orthotopically transplanted into CBA/J (H-2k) recipients. Donor animals received a single dose of PHD-inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40mg/kg i.p.) or vehicle control 4h before transplantation. Transplanted tracheas were harvested 14 or 30days after transplantation and were analyzed by histology, by immunofluorescence and by rtPCR for mRNA expression.
  
  
  
  Donor pre-conditioning with ICA resulted in HIF accumulation and induction of HIF target genes: HO-1, VEGF, MIF, TGFβ, and EpoR, which persisted during different times of ischemia. Grafts of vehicle treated controls showed substantially more luminal obliteration on postoperative day 30 in contrast to groups pre-treated with ICA [luminal obliteration 29.2±5% (ICA) vs. 36.7±8% (control), p<0.01]. We found significantly lower expression of TNFα, PDGFß, MCP-1, E-selectin, and ICAM-1 14days after ICA premedication. In addition ICA pre-treated groups revealed decreased T-cell and macrophage infiltration in tracheal grafts on days 30 after transplantation (p<0.05).
  
  
  
  Pre-treatment with ICA effectively reduced obliterative bronchiolitis. Our data suggest that activation of hypoxia-inducible transcription factors (HIFs) and thereby adaptation to low oxygen prevents the development of OB and allograft injury. Pharmaceutical inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves further clinical evaluation.
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. Electronic address: christian.heim@uk-erlangen.de.
authors: Christian
authors: C
authors: Heim
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Benjamin
authors: B
authors: Motsch
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Sabina
authors: S
authors: Jalilova
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Wanja M
authors: WM
authors: Bernhardt
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Martina
authors: M
authors: Ramsperger-Gleixner
authors: Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Nicolai
authors: N
authors: Burzlaff
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Michael
authors: M
authors: Weyand
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: Kai-Uwe
authors: KU
authors: Eckardt
authors: Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Heart and Diabetes Center NRW, Department of Thoracic and Cardiovascular Surgery, Ruhr-University Bochum, Bad Oeynhausen, Germany.
authors: Stephan M
authors: SM
authors: Ensminger
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy*; D002465:Cell Movement; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D007546:Isoquinolines / Q000627:therapeutic use*; D016040:Lung Transplantation; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D023421:Models, Animal; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D019172:Transplantation Conditioning / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C000608512:2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido)acetic acid; D000893:Anti-Inflammatory Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007546:Isoquinolines; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D064800:Prolyl-Hydroxylase Inhibitors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D005998:Glycine
keywords: HIF; Hypoxia-inducible transcription factors; Obliterative bronchiolitis