Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

Xinguo Jiang, Mohammad A. Khan, Wen Tian, Joshua Beilke, Ramesh Natarajan, Jon Kosek, Mervin Yoder, Gregg L. Semenza, Mark R. Nicolls

Research output: Contribution to journalArticle

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Abstract

Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1a mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection.

Original languageEnglish
Pages (from-to)2336-2349
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number6
DOIs
StatePublished - Jun 1 2011

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Microvessels
Adenoviridae
Allografts
Transplants
Bronchiolitis
Genes
Perfusion
Airway Remodeling
Lung Transplantation
Vascular Endothelial Growth Factor A
Blood Vessels
Fibrosis
Ischemia
Transplantation
Epithelial Cells
Lung
Health
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. / Jiang, Xinguo; Khan, Mohammad A.; Tian, Wen; Beilke, Joshua; Natarajan, Ramesh; Kosek, Jon; Yoder, Mervin; Semenza, Gregg L.; Nicolls, Mark R.

In: Journal of Clinical Investigation, Vol. 121, No. 6, 01.06.2011, p. 2336-2349.

Research output: Contribution to journalArticle

Jiang, Xinguo ; Khan, Mohammad A. ; Tian, Wen ; Beilke, Joshua ; Natarajan, Ramesh ; Kosek, Jon ; Yoder, Mervin ; Semenza, Gregg L. ; Nicolls, Mark R. / Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 6. pp. 2336-2349.
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