Spectrum of chronic lung allograft pathology in a mouse minor-mismatched orthotopic lung transplant model
Spectrum of chronic lung allograft pathology in a mouse minor-mismatched orthotopic lung transplant model
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DOI：
10.1111/ajt.15167
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发表时间：
2019-01-01
影响因子：
8.8
通讯作者：
Keshavjee, Shaf
中科院分区：
文献类型：
--
作者：
Martinu, Tereza;Oishi, Hisashi;Keshavjee, Shaf
慢性肺移植物功能障碍（CLAD）是限制肺移植（LTx）后生存的致命疾病。CLAD的病理标志是闭塞性细支气管炎（OB）。一部分患者表现出更具侵袭性的CLAD表型，称为限制性同种异体移植综合征（RAS），其特征是肺实质纤维化（PF）。小鼠原位单个LTx模型已被证明与同种异体移植物损伤的机制研究相关。据报道，使用C57 BL/10（B10）供体和C57 BL/6（B6）受体的次要同种异体抗原错配菌株组合导致OB。认识到OB严重程度是可能与包括PF在内的其他病理共存的谱，我们旨在表征和量化该模型中CLAD的病理特征。左侧LTx以以下组合进行：B10 -> B6，B6 -> B10，B6 -> B6。移植后4周，盲法病理半定量评估显示，OB存在于66%的B10 -> B6和30%的B6 -> B10移植物中。大多数患有OB的小鼠也有PF，具有胸膜实质纤维弹性组织增生症的模式，这让人联想到人类RAS相关的病理学。病理变化的分级显示气道纤维化、PF、急性排斥反应、血管纤维化和上皮变化的不同严重程度，与在人CLAD中观察到的相似。这些评估可以使小鼠LTx模型成为进一步研究CLAD发病机制的更有用的工具。
Chronic lung allograft dysfunction (CLAD) is a fatal condition that limits survival after lung transplantation (LTx). The pathological hallmark of CLAD is obliterative bronchiolitis (OB). A subset of patients present with a more aggressive CLAD phenotype, called restrictive allograft syndrome (RAS), characterized by lung parenchymal fibrosis (PF). The mouse orthotopic single LTx model has proven relevant to the mechanistic study of allograft injury. The minor-alloantigen-mismatched strain combination using C57BL/10(B10) donors and C57BL/6(B6) recipients reportedly leads to OB. Recognizing that OB severity is a spectrum that may coexist with other pathologies, including PF, we aimed to characterize and quantify pathologic features of CLAD in this model. Left LTx was performed in the following combinations: B10 -> B6, B6 -> B10, B6 -> B6. Four weeks posttransplant, blinded pathologic semi-quantitative assessment showed that OB was present in 66% of B10 -> B6 and 30% of B6 -> B10 grafts. Most mice with OB also had PF with a pattern of pleuroparenchymal fibroelastosis, reminiscent of human RAS-related pathology. Grading of pathologic changes demonstrated variable severity of airway fibrosis, PF, acute rejection, vascular fibrosis, and epithelial changes, similar to those seen in human CLAD. These assessments can make the murine LTx model a more useful tool for further mechanistic studies of CLAD pathogenesis.