Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, California, USA.
J Clin Invest. 2011 Jun;121(6):2336-49. doi: 10.1172/JCI46192. Epub 2011 May 23.
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.
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，肺移植中涉及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。在这里，我们发现在原位气管移植模型中，HIF-1α 介导气道微血管修复。条件性敲除 Hif1a 的移植物中，募集到同种异体移植物的受体衍生的 Tie2+血管生成细胞减少，损伤的微血管修复受损，微血管灌注迅速丧失，上皮细胞迅速剥脱。相比之下，通过腺病毒载体诱导的移植物 HIF-1α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恢复的时间窗口，并减轻了气道纤维化重塑。HIF-1α 过表达诱导了促血管生成因子如 Sdf1、Plgf 和 Vegf 的表达，并促进了血管修复性 Tie2+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方法可能促进移植物的健康并预防慢性排斥反应。
