Reduction of Obliterative Bronchiolitis (OB) by PHD (Prolyl-hydroxylase)-inhibitors activating Hypoxia-inducible transcription factors (HIFs) in an experimental mouse model

Purpose: Obliterative Bronchitis (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 (H2(b)) donor tracheas were orthotopically transplanted into CBA (H2(k)) recipients. Donor animals received a single dose of PHD-inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40 mg/kg i.p.) or vehicle 4h before transplantation (n = 7). Animals were harvested 30 days after transplantation for analysis by histology as well as by immunofluorescence and on day 14 for PCR and mRNA expression.

Results: Donor preconditioning with ICA resulted in HIF accumulation and induction of HIF target genes, which persisted during the entire experimental protocol. Vehicle treated controls showed substantial luminal obliteration on postoperative day 30 in contrast to groups pre-treated with ICA [37.8 ± 8.0% (control) vs. 28.4 ± 5.0% (ICA), P = 0.01]. There was also significantly lower intra-graft expression of IFNγ, TGFß, MCP1, and E-Selectin after ICA premedication.

Conclusions: Pre-treatment with ICA substantially reduces Obliterative Bronchiolitis. These data suggest that activation of Hypoxia-inducible transcription factors (HIFs) and hereby adaptation to low oxygen prevents the development of OB and therefore allograft injury. Pharmaceutical inhibition of PHDs appears to be a very attractive strategy for organ preservation that deserves further clinical evaluation.