Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse

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• 作者：Jussi O. Ropponen ; MD^a ; ^b ; ^{jussi.o.ropponen@helsinki.fi" class="auth_mail" title="E-mail the corresponding author} ; Mikko A. Kerä ; nen ; MD ; PhD^a ; Alireza Raissadati ; MD^a ; Antti I. Nykä ; nen ; MD ; PhD^a ; ^b ; Rainer Krebs ; MSc ; PhD^a ; Karl B. Lemströ ; m ; MD ; PhD^a ; ^b ; Jussi M. Tikkanen ; MD ; PhD^a ; ^b
• 关键词：hypoxia-inducible factor-1 ; obliterative bronchiolitis ; lung transplantation ; Von Hippel-Lindau protein ; allograft rejection
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：35
• 期：5
• 页码：671-678
• 全文大小：1254 K

文摘

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.

Methods

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.

Results

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.

Conclusions

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.