Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
Xinguo Jiang, … , Gregg L. Semenza, Mark R. Nicolls
Xinguo Jiang, … , Gregg L. Semenza, Mark R. Nicolls
Published May 23, 2011
Citation Information: J Clin Invest. 2011;121(6):2336-2349. https://doi.org/10.1172/JCI46192.
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Research Article

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

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-1α 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.

Authors

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

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Figure 8

Model of how HIF-1α promotes airway microvascular repair and prevents fibrosis.

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Model of how HIF-1α promotes airway microvascular repair and prevents fi...
(A) Scheme of recipient-derived Tie2+ cells contributing to microvascular repair in allograft rejection. Increased allograft hypoxia during rejection leads to increased expression of HIF-1α in endothelial cells, which further induces expression of proangiogenic factors that promote the recruitment and retention of recipient-derived angiogenic cells, including Tie2+ cells (green) and other non-Tie2+ cells (yellow). Enhanced expression of HIF-1α accelerates vascular repair. (B) Scheme of the effects of HIF-1α gene overexpression on airway perfusion and fibrosis. Perfusion is reestablished at day 4 following transplantation in both AdLacZ- and AdCA5-treated OTT after microvascular reconnection between the donor and the recipient. Progressive microvascular damage leads to a complete loss of perfusion at around day 10, followed by a partial microvascular reestablishment at day 21 in AdLacZ-treated allografts. Reestablished microvessels are phenotypically distinct from normal ones. In contrast, microvascular perfusion is prolonged to day 12 in AdCA5-treated allografts. This anatomic finding identifies day-12 allografts as “rescuable” to normal architecture by immunosuppression (versus day 8 for control airways; blue line). The onset and the intensity of the collagen deposition are significantly delayed and diminished respectively in AdCA5-treated airways (red line). Alleviation of fibrosis in HIF-1α–overexpressed airways is likely due to the decreased burden of tissue hypoxia (ischemia × time duration), which is represented by the yellow area.