Maintenance of airway epithelium in acutely rejected orthotopic vascularized mouse lung transplants
Maintenance of airway epithelium in acutely rejected orthotopic vascularized mouse lung transplants
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DOI：
10.1165/rcmb.2007-0257rc
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发表时间：
2007-12-01
影响因子：
6.4
通讯作者：
Kreisel, Daniel
中科院分区：
文献类型：
--
作者：
Okazaki, Mikio;Gelman, Andrew E.;Kreisel, Daniel
肺移植仍然是许多患有终末期肺病的患者的唯一治疗选择。肺移植后的长期成功受到闭塞性细支气管炎的严重限制。小鼠异位气管移植模型已被广泛用于研究闭塞性气道疾病的发病机制和预防其发展的免疫抑制策略。尽管它的实用性，该模型采用近端气道，缺乏气流和不血管化。我们已经开发了一种新的小鼠原位血管化肺移植模型，该模型导致同种异体品系组合的严重血管排斥反应。在此，我们描述了28天内非免疫抑制异位气管和血管化肺移植模型中气道上皮细胞命运的差异。在两种模型中，被认为对气道纤维化和间质胶原沉积的发展至关重要的生长因子的上调是相似的。然而，虽然气管模型中发生气道上皮细胞的损失，气道上皮细胞保持完整和完全分化的肺同种异体移植物，尽管深刻的血管排斥反应。此外，我们还证实了抗凋亡蛋白Bcl-2在急性排斥肺移植物气道上皮细胞中的表达。这些发现表明，除了同种免疫反应，其他刺激可能需要气道上皮细胞的破坏。因此，血管化小鼠肺移植模型可能为研究同种异体肺移植气道病理的免疫和非免疫机制之间的相互作用提供新的、更符合生理学的实验工具。
Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial Collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the antiapoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli maybe required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide anew and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts.