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异位气管移植后闭塞性细支气管炎中移植物的血管再生

Revascularization of the graft in obliterative bronchiolitis after heterotopic tracheal transplantation.

作者信息

Nemska Simona, Daubeuf François, Frossard Nelly

机构信息

Laboratoire d'Innovation Thérapeutique, Unité Mixte de Recherche 7200 Centre National de la Recherche Scientifique-Université de Strasbourg and Laboratoire d'Excellence MEDALIS Faculté de Pharmacie, Illkirch, France.

Laboratoire d'Innovation Thérapeutique, Unité Mixte de Recherche 7200 Centre National de la Recherche Scientifique-Université de Strasbourg and Laboratoire d'Excellence MEDALIS Faculté de Pharmacie, Illkirch, France

出版信息

Physiol Rep. 2016 Feb;4(4). doi: 10.14814/phy2.12690.

Abstract

Obliterative bronchiolitis is the principal long-term problem for lung transplant patients. One of the simplest and most reproducible animal models of obliterative bronchiolitis is heterotopic tracheal transplantation in subcutaneous tissue, where the graft is not primarily vascularized. We demonstrate here the rapid graft revascularization and the kinetics of expression of its angiogenic and lymphatic factors. We performed iso- and allotracheal transplantations harvested on day 0-21. The number of functional blood vessels, quantified after intravenous biotinylated dextran administration, increased from D0 (0 for both iso- and allografts) to D21 (44 ± 8 vessels/mm(2) in isografts and 22 ± 3 in allografts, P < 0.001 for both vs. D0). VEGF mRNA expression assessed by qPCR peaked on D1 (4.3-fold increase in isografts and 4.0-fold in allografts, P < 0.0001 for both vs. D0), but receded thereafter. Angiopoietin-1, involved in the maturation of the neoformed vessels, increased later on, by 6.2-fold (P < 0.05) in isografts and 11.5-fold in allografts (P < 0.001) by D21, and angiopoietin-2 by 7.8-fold in isografts (P < 0.05) and 13.8-fold in allografts (P < 0.01). Although always present in the iso- and allografts, there were significantly more and larger LYVE1(+) lymphatic vessels at D21 in allografts than in isografts. Thus, we demonstrate that tracheal grafts are rapidly revascularized by functional blood and lymphatic vessels, due to early VEGF and subsequent angiopoietins expression, which is a new advantage of this model, in addition to its ease of use, reproducibility, and viability in the absence of immunosuppressive treatment.

摘要

闭塞性细支气管炎是肺移植患者主要的长期问题。闭塞性细支气管炎最简单且最可重复的动物模型之一是皮下组织中的异位气管移植,在此移植中移植物最初没有血管化。我们在此展示了移植物的快速血管再生及其血管生成和淋巴管生成因子的表达动力学。我们进行了在第0 - 21天收获的同基因和异基因气管移植。在静脉注射生物素化葡聚糖后定量的功能性血管数量,从第0天(同基因和异基因移植均为0)增加到第21天(同基因移植为44±8条血管/mm²,异基因移植为22±3条血管/mm²,两者与第0天相比P均<0.001)。通过qPCR评估的VEGF mRNA表达在第1天达到峰值(同基因移植增加4.3倍,异基因移植增加4.0倍,两者与第0天相比P均<0.0001),但此后下降。参与新生血管成熟的血管生成素-1随后增加,到第21天同基因移植增加6.2倍(P<0.05),异基因移植增加11.5倍(P<0.001),血管生成素-2在同基因移植中增加7.8倍(P<0.05),在异基因移植中增加13.8倍(P<0.01)。尽管同基因和异基因移植中始终存在LYVE1(+)淋巴管,但在第21天异基因移植中的LYVE1(+)淋巴管数量明显多于同基因移植且管径更大。因此,我们证明气管移植物通过功能性血管和淋巴管快速实现血管再生,这归因于早期VEGF及随后血管生成素的表达,这是该模型的一个新优势,此外它还具有易于使用、可重复性以及在无免疫抑制治疗情况下的存活能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc17/4816893/e77ab9b266af/PHY2-4-e12690-g001.jpg

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