Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
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DOI：
10.1172/jci46192
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Nicolls, Mark R.
中科院分区：
文献类型：
--
作者：
Jiang, Xinguo;Khan, Mohammad A.;Nicolls, Mark R.
慢性排斥反应，表现为小气道纤维化（闭塞性细支气管炎[OB]），是肺移植长期存活的主要障碍。最近的研究表明，参与肺移植的气道在基线时相对缺氧，OB的发病机制可能与气道微血管短暂丧失引起的缺血有关。在此，我们在原位气管移植模型中显示HIP-1 α介导气道微血管修复。有条件敲除Hif 1a的移植物表现出减少了对同种异体移植物来源的Tier（2+）血管生成细胞的招募，受损微血管的修复受损，微血管灌注的加速损失，以及上皮细胞的加速剥脱。相比之下，通过腺病毒载体诱导的移植物HIP-1 α过表达延长了气道微血管灌注，保持了上皮完整性，延长了移植物从慢性排斥中获救的时间窗，并减弱了气道纤维化重塑。HIP-1 α过表达诱导促血管生成因子如Sdf 1、Plgf和Vegf的表达;并促进血管修复Tier（2+）细胞的募集。这项研究表明，在急性排斥反应期间增强血管完整性的治疗可以促进移植物健康并预防慢性排斥反应。
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 HIP-1 alpha mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tier(2+) angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIP-1 alpha 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. HIP-1 alpha overexpression induced the expression of pro-angiogenic factors such as Sdf1, Plgf, and Vegf; and promoted the recruitment of vasoreparative Tier(2+) cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection.