Local, Origin of Mesenchymal Cells in a Murine Orthotopic Lung Transplantation Model of Bronchiolitis Obliterans
Local, Origin of Mesenchymal Cells in a Murine Orthotopic Lung Transplantation Model of Bronchiolitis Obliterans
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DOI：
10.1016/j.ajpath.2015.03.002
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发表时间：
2015-06-01
影响因子：
6
通讯作者：
Lama, Vibha N.
中科院分区：
文献类型：
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作者：
Mimura, Takeshi;Walker, Natalie;Lama, Vibha N.
闭塞性细支气管炎是肺移植受者慢性移植物衰竭和长期死亡的主要原因。在这里，我们使用了一种新的小鼠模型来表征全肺微环境中的同种异体移植物纤维化。在不同程度的主要组织相容性复合体错配组合的小鼠中进行单侧左肺移植。B6 D2 F1/J（C57 BL/6 J和DBA/2 J之间的杂交）（单倍型H2 b/d）移植到DBA/2 J（H2 d）受体中的肺被鉴定为在所有同种异体移植物中显示闭塞性细支气管炎的组织病理学。时程分析显示，从第14天细支气管和血管的免疫细胞浸润（与急性排斥反应和淋巴细胞性支气管炎一致）到第28天闭塞性细支气管炎的上皮下和管腔内纤维化病变的演变。第28天同种异体移植物的羟脯氨酸含量显著高于同种异体移植物（33.21 +/- 1.89 vs 22.36 +/- 2.33 μ g/mL）。在第40天，羟脯氨酸含量进一步增加（48.91 +/- 7.09 μ g/mL）。流式细胞术分析用于研究纤维化同种异体移植物中间充质细胞的来源。第28天同种异体移植物中的I型胶原阳性细胞（89.43% +/- 6.53%）为H2 Db阳性，表明其来源于供体。这种新的小鼠模型在单肺移植的背景下显示出一致的和可重复的同种异体移植物纤维化，并代表了在研究慢性移植物衰竭机制方面的重大进展。
Bronchiolitis obliterans is the Leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left Lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) Lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 +/- 1.89 versus 22.36 +/- 2.33 mu g/mL). At day 40 the hydroxyproline content had increased further (48.91 +/- 7.09 mu g/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I-positive cells (89.43% +/- 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure.