al-Dossari G A, Kshettry V R, Jessurun J, Bolman R M
Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis 55455-0392.
Ann Thorac Surg. 1994 Jul;58(1):34-9; discussion 39-40. doi: 10.1016/0003-4975(94)91068-5.
Obliterative bronchiolitis is a major cause of long-term morbidity after lung transplantation. It is characterized by small-airway inflammation and occlusion by fibrous tissue. The pathogenesis is uncertain. To study this disease, we developed a model of posttransplantation obliterative bronchiolitis using genetically defined miniature swine. Group 1 (n = 2) received a left lung autograft; group 2 (n = 7), a left lung allograft. Group 2 recipients were given cyclosporine, prednisone, and azathioprine for 3 months, then immunosuppression was tapered and discontinued over 1 month. The animals were observed for an additional 2 months, then sacrificed. Lung grafts in both groups were monitored with serial bronchoalveolar lavages and transbronchial biopsies for 6 months. After sacrifice, lung grafts underwent histopathologic and immunohistochemical examination. No allograft had histologic evidence of acute rejection or peribronchiolar infiltrate during the first 3 months of immunosuppression. During the tapering period, airway changes characterized by severe peribronchiolar lymphocytic infiltrates were seen. Bronchoalveolar lavages of allografts showed significantly increased lymphocyte counts with CD8+ cells predominating. After the discontinuation of immunosuppression, transbronchial biopsy and autopsy specimens showed progressive fibrous inflammatory occlusion of bronchioles. Immunohistochemical staining demonstrated increased expression of MCH class II antigen on the bronchiolar epithelium and increased dendritic cells and CD4+ lymphocytes. None of these changes were seen in group 1. Our findings suggest obliterative bronchiolitis is an immunologically mediated phenomenon related to chronic graft rejection after lung transplantation. This model will allow systematic study of the pathogenesis of obliterative bronchiolitis and possible therapeutic intervention.
闭塞性细支气管炎是肺移植后长期发病的主要原因。其特征为小气道炎症和纤维组织阻塞。发病机制尚不清楚。为研究该疾病，我们利用基因明确的小型猪建立了移植后闭塞性细支气管炎模型。第1组（n = 2）接受左肺自体移植；第2组（n = 7）接受左肺同种异体移植。第2组受体接受环孢素、泼尼松和硫唑嘌呤治疗3个月，然后在1个月内逐渐减少并停用免疫抑制。对动物再观察2个月，然后处死。两组的肺移植均通过连续支气管肺泡灌洗和经支气管活检监测6个月。处死动物后，对肺移植进行组织病理学和免疫组织化学检查。在免疫抑制的前3个月，没有同种异体移植有急性排斥或支气管周围浸润的组织学证据。在免疫抑制逐渐减少期间，可见以严重支气管周围淋巴细胞浸润为特征的气道变化。同种异体移植的支气管肺泡灌洗显示淋巴细胞计数显著增加，以CD8 +细胞为主。停用免疫抑制后，经支气管活检和尸检标本显示细支气管逐渐出现纤维性炎性阻塞。免疫组织化学染色显示细支气管上皮上MCH II类抗原表达增加，树突状细胞和CD4 +淋巴细胞增加。第1组未观察到这些变化。我们的研究结果表明，闭塞性细支气管炎是一种与肺移植后慢性移植物排斥相关的免疫介导现象。该模型将允许对闭塞性细支气管炎的发病机制和可能的治疗干预进行系统研究。
