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

Heim C, Motsch B, Jalilova S, Bernhardt WM, Ramsperger-Gleixner M, Burzlaff N, Weyand M, Eckardt KU, Ensminger S (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Transplant Immunology Elsevier

Book Volume: 39

Pages Range: 66-73

DOI: 10.1016/j.trim.2016.08.007

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-2(b)) donor tracheas were orthotopically transplanted into CBA/J (H-2(k)) 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, TGF?, 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 TNF?, 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 with CRIS profile

Christian Heim Department of Cardiac Surgery Martina Ramsperger-Gleixner Department of Cardiac Surgery Nicolai Burzlaff Professur für Anorganische Chemie Michael Weyand Lehrstuhl für Herzchirurgie Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Ruhr-Universität Bochum (RUB) DE Germany (DE)

How to cite

APA:

Heim, C., Motsch, B., Jalilova, S., Bernhardt, W.M., Ramsperger-Gleixner, M., Burzlaff, N.,... Ensminger, S. (2016). Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model. Transplant Immunology, 39, 66-73. https://dx.doi.org/10.1016/j.trim.2016.08.007

MLA:

Heim, Christian, et al. "Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model." Transplant Immunology 39 (2016): 66-73.

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