Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
J Thorac Cardiovasc Surg. 2014 Jul;148(1):245-53. doi: 10.1016/j.jtcvs.2013.08.046. Epub 2013 Sep 29.
Surgical and catheter-based interventions on pulmonary veins are associated with pulmonary vein stenosis (PVS), which can progress diffusely through the "upstream" pulmonary veins. The mechanism has been rarely studied. We used a porcine model of PVS to assess disease progression with emphasis on the potential role of endothelial-mesenchymal transition (EndMT).
Neonatal piglets underwent bilateral pulmonary vein banding (banded, n = 6) or sham operations (sham, n = 6). Additional piglets underwent identical banding and stent implantation in a single-banded pulmonary vein 3 weeks postbanding (stented, n = 6). At 7 weeks postbanding, hemodynamics and upstream PV pathology were assessed.
Banded piglets developed pulmonary hypertension. The upstream pulmonary veins exhibited intimal thickening associated with features of EndMT, including increased transforming growth factor (TGF)-β1 and Smad expression, loss of endothelial and gain of mesenchymal marker expression, and coexpression of endothelial and mesenchymal markers in banded pulmonary vein intimal cells. These immunopathologic changes and a prominent myofibroblast phenotype in the remodeled pulmonary veins were consistently identified in specimens from patients with PVS, in vitro TGF-β1-stimulated cells isolated from piglet and human pulmonary veins, and human umbilical vein endothelial cells. After stent implantation, decompression of a pulmonary vein was associated with reappearance of endothelial marker expression, suggesting the potential for plasticity in the observed pathologic changes, followed by rapid in-stent restenosis.
Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.
肺静脉的外科和导管介入治疗与肺静脉狭窄（PVS）有关，PVS 可通过“上游”肺静脉弥漫性进展。该机制很少被研究。我们使用 PVS 的猪模型来评估疾病进展，重点研究内皮-间充质转化（EndMT）的潜在作用。
新生仔猪接受双侧肺静脉结扎（结扎组，n=6）或假手术（假手术组，n=6）。另外 6 只仔猪在结扎后 3 周进行相同的结扎和支架植入术。在结扎后 7 周，评估血流动力学和上游 PV 病理。
结扎组仔猪出现肺动脉高压。上游肺静脉出现内膜增厚，伴有 EndMT 的特征，包括 TGF-β1 和 Smad 表达增加、内皮标志物丢失和间充质标志物获得，以及结扎肺静脉内膜细胞中内皮和间充质标志物的共表达。这些免疫病理变化以及在 PVS 患者、从仔猪和人肺静脉分离的 TGF-β1 刺激细胞以及人脐静脉内皮细胞中观察到的重塑肺静脉中的突出成纤维细胞表型，在体外均一致地被识别。支架植入后，肺静脉减压与内皮标志物表达的重新出现相关，表明观察到的病理变化具有潜在的可塑性，随后迅速发生支架内再狭窄。
在仔猪中进行的新生肺静脉结扎重现了临床 PVS 的关键方面，并强调了与 EndMT 一致的病理特征，支持评估旨在利用上游肺静脉病理可逆性的治疗策略的合理性。
