Atanasova Srebrena, Hirschburger Markus, Jonigk Danny, Obert Martin, Petri Kathrin, Evers Alena, Hecker Andreas, Schmitz Jessica, Kaufmann Andreas, Wilhelm Jochen, Chakraborty Trinad, Warnecke Gregor, Gottlieb Jens, Padberg Winfried, Grau Veronika
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Member of the German Center for Lung Research (DZL).
J Heart Lung Transplant. 2013 Nov;32(11):1131-9. doi: 10.1016/j.healun.2013.07.016. Epub 2013 Sep 16.
The long-term success of human lung transplantation is limited by the development of bronchiolitis obliterans syndrome. Acute rejection episodes and infections are important risk factors and seem to play major pathogenic roles. We established a relevant experimental model that mimics important aspects of human bronchiolitis obliterans syndrome.
The Fischer 344-to-Lewis rat strain combination was used for orthotopic left lung transplantation. Isogeneic transplantations were performed in the Lewis rat. Recipients were treated with ciclosporin for 10 days. Lipopolysaccharide or vehicle was instilled into the airways 28 days after transplantation. Grafts were monitored by computed tomography, and recipients were euthanized on Days 28-90. The messenger RNA expression of selected chemokines and their receptors was measured on Days 28, 29, 33, 40 after transplantation. Graft histopathology on Day 90 was compared with lungs from patients who underwent re-transplantation due to end-stage allograft dysfunction.
Lung allografts treated with ciclosporin and vehicle only sporadically displayed tissue remodeling. In contrast, lipopolysaccharide treatment induced severe inflammation. In the long-term, severe vascular remodeling, lung fibrosis, and fibroproliferative remodeling of airways were found that closely resemble the histopathologic changes in grafts from human patients with bronchiolitis obliterans syndrome. Chronic damage was virtually absent from pulmonary isografts and native right lungs. Chemokine (C-C motif) ligand 5 and chemokine (C-X-C motif) ligand 9-11, and their receptors, were over-expressed in allografts.
Our experimental model mirrors key aspects of human bronchiolitis obliterans syndrome. It will be useful to elucidate its pathogenesis and to develop therapeutic approaches improving the long-term outcome of human lung transplantation.
闭塞性细支气管炎综合征的发展限制了人类肺移植的长期成功。急性排斥反应和感染是重要的风险因素，似乎起着主要的致病作用。我们建立了一个模拟人类闭塞性细支气管炎综合征重要方面的相关实验模型。
采用Fischer 344到Lewis大鼠品系组合进行原位左肺移植。在Lewis大鼠中进行同基因移植。受体用环孢素治疗10天。移植后28天向气道内滴注脂多糖或赋形剂。通过计算机断层扫描监测移植物，并在第28 - 90天对受体实施安乐死。在移植后第28、29、33、40天测量选定趋化因子及其受体的信使核糖核酸表达。将第90天的移植物组织病理学与因终末期移植物功能障碍而接受再次移植的患者的肺进行比较。
仅用环孢素和赋形剂治疗的肺同种异体移植物偶尔出现组织重塑。相比之下，脂多糖治疗引发了严重炎症。长期来看，发现严重的血管重塑、肺纤维化和气道纤维增生性重塑，与人类闭塞性细支气管炎综合征患者移植物中的组织病理学变化非常相似。肺同基因移植物和天然右肺几乎没有慢性损伤。趋化因子（C - C基序）配体5和趋化因子（C - X - C基序）配体9 - 11及其受体在同种异体移植物中过度表达。
我们的实验模型反映了人类闭塞性细支气管炎综合征的关键方面。这将有助于阐明其发病机制，并开发改善人类肺移植长期结果的治疗方法。
