Details

Autor(en) / Beteiligte

• Heim, Christian
• Motsch, Benjamin
• Jalilova, Sabina
• Bernhard, Wanja
• Ramsperger-Gleixner, Martina
• Burzlaff, Nicolai
• Weyand, Michael
• Eckardt, Kai-Uwe
• Ensminger, Stephan M

Titel

Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model

Ist Teil von

• Transplant immunology, 2016-11, Vol.39, p.66-73

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract Background 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. Methods 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. Animals were harvested 14, respectively 30 days after transplantation and grafts were analyzed by histology, mRNA expression and immunofluorescence. Results 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. Vehicle treated controls showed substantial 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 < .01]. We found significantly lower expression of TNFα, PDGFß, MCP-1, E-selectin, and ICAM-1 14 days 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 < .05). Conclusion 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.