Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation.
Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation.
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肺和干细胞移植后细支气管炎的形态和分子基序的比较分析和肺泡纤维弹性。
DOI：
10.1002/cjp2.60
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Laenger F
中科院分区：
文献类型：
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作者：
Jonigk D;Rath B;Borchert P;Braubach P;Maegel L;Izykowski N;Warnecke G;Sommer W;Kreipe H;Blach R;Anklamm A;Haverich A;Eder M;Stadler M;Welte T;Gottlieb J;Kuehnel M;Laenger F
慢性同种异体肺移植功能障碍（CLAD）仍然是肺移植（LuTx）后长期生存的主要障碍。形态学上，CLAD 的定义是小气道的闭塞性重塑（闭塞性细支气管炎，BO）以及最近描述的肺泡胶原闭塞伴弹性组织变性，概括为肺泡弹力纤维变性（AFE）。这两种模式不仅限于同种异体肺移植，在造血干细胞移植（HSCT）和放射化疗（RC）后也有报道。在本研究中，我们利用传统组织病理学、激光显微切割、PCR 技术和免疫组织化学，对人类 CLAD (n = 22)、HSCT (n = 29) 和 RC (n = 6) 肺外植体中的 BO 和 AFE 病变进行区室特异性形态学和分子分析，利用传统组织病理学、激光显微切割、PCR 技术和免疫组织化学来评估纤维化相关基因和蛋白表达。我们对纤维化相关基因的分析得出了三个关键结果：（i）一般来说，“BO 就是 BO”。尽管临床背景不同，但所有组的 BO 病变的分子特征都是相似的。 (ii) “AFE 就是 AFE”。在因 AFE 导致肺部生理学发生限制性变化的所有患者组中，存在大部分（但并非绝对）相同的基因表达模式。 iii) LuTx 后与 AFE 相伴的 BO 具有类似 AFE 的分子微环境，这是 (i) 的唯一例外。此外，我们描述了 AFE 模式的进化模型：对损伤模式的非特异性富含纤维蛋白的反应会引发错误的解决尝试，并最终进展为明显的 AFE。我们的数据表明缺乏经典的纤溶酶和通过巨噬细胞的替代纤维蛋白降解机制，导致纤维重塑和限制性功能变化。这些数据可作为诊断辅助手段，有助于预测 LuTx 和 HSCT 患者呼吸功能障碍的临床病程。此外，对纤维蛋白溶解和纤维形成机制的分析可能会揭示潜在的治疗靶点，以改变最终致命的肺重塑的过程。
Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long‐term survival following lung transplantation (LuTx). Morphologically CLAD is defined by obliterative remodelling of the small airways (bronchiolitis obliterans, BO) as well as a more recently described collagenous obliteration of alveoli with elastosis summarised as alveolar fibroelastosis (AFE). Both patterns are not restricted to pulmonary allografts, but have also been reported following haematopoietic stem cell transplantation (HSCT) and radio chemotherapy (RC). In this study we performed compartment‐specific morphological and molecular analysis of BO and AFE lesions in human CLAD (n = 22), HSCT (n = 29) and RC (n = 6) lung explants, utilising conventional histopathology, laser‐microdissection, PCR techniques and immunohistochemistry to assess fibrosis‐associated gene and protein expression. Three key results emerged from our analysis of fibrosis‐associated genes: (i) generally speaking, “BO is BO”. Despite the varying clinical backgrounds, the molecular characteristics of BO lesions were found to be alike in all groups. (ii) “AFE is AFE”. In all groups of patients suffering from restrictive changes to lung physiology due to AFE there were largely – but not absolutely ‐ identical gene expression patterns. iii) BO concomitant to AFE after LuTx is characterised by an AFE‐like molecular microenvironment, representing the only exception to (i). Additionally, we describe an evolutionary model for the AFE pattern: a non‐specific fibrin‐rich reaction to injury pattern triggers a misguided resolution attempt and eventual progression towards manifest AFE. Our data point towards an absence of classical fibrinolytic enzymes and an alternative fibrin degrading mechanism via macrophages, resulting in fibrous remodelling and restrictive functional changes. These data may serve as diagnostic adjuncts and help to predict the clinical course of respiratory dysfunction in LuTx and HSCT patients. Moreover, analysis of the mechanism of fibrinolysis and fibrogenesis may unveil potential therapeutic targets to alter the course of the eventually fatal lung remodelling.