King M B, Jessurun J, Savik S K, Murray J J, Hertz M I
Department of Internal Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Transplantation. 1997 Feb 27;63(4):528-32. doi: 10.1097/00007890-199702270-00007.
Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologically by fibroproliferation within small airways. The pathogenesis of OB is thought to involve chronic allograft rejection, and therapy frequently includes augmentation of immunosuppression. We have developed a model that reproduces the pathologic lesion of OB and allows study of interventions designed to limit airway fibrosis. In this model, heterotopic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the airway lumen, changes not seen in heterotopic isografts. Cyclosporine (CsA) inhibits activation and proliferation of T lymphocytes and is commonly administered after lung transplantation. We hypothesized that use of CsA in our model system would reduce fibroproliferation in tracheal allografts. To test this hypothesis, murine tracheas were transplanted heterotopically into allo matched and allomismatched recipients, and then treated with varying doses (5, 10, 15, or 25 mg/kg i.p. q.d.) of CsA. Controls included allografts and isografts not treated with CsA. After 30 days, tracheas were harvested and examined histologically. CsA markedly reduced the development of fibroproliferation in allografts (19% in treated allografts versus 90% in untreated allografts, P<0.0001), but did not reduce inflammation or airway epithelial cell injury. High-dose (25 mg/kg/day) CsA was more effective than lower doses in reducing fibroproliferation (0% in high dose versus 29% in low dose, P=0.04). These findings demonstrate that CsA significantly reduces development of the pathologic lesion of OB, and supports the role of alloimmunity in the pathogenesis of this disease.
闭塞性细支气管炎（OB）是肺移植受者长期存活的重要威胁，其组织学特征是小气道内纤维组织增生。OB的发病机制被认为与慢性移植物排斥反应有关，治疗通常包括增加免疫抑制。我们已经建立了一个模型，该模型重现了OB的病理病变，并允许研究旨在限制气道纤维化的干预措施。在这个模型中，将小鼠气道异位移植到免疫不匹配的受体中会导致气道腔内上皮异常和纤维组织增生，而异位同基因移植中则不会出现这些变化。环孢素（CsA）可抑制T淋巴细胞的活化和增殖，常用于肺移植后。我们假设在我们的模型系统中使用CsA会减少气管同种异体移植物中的纤维组织增生。为了验证这一假设，将小鼠气管异位移植到同种匹配和同种不匹配的受体中，然后用不同剂量（5、10、15或25mg/kg腹腔注射，每日一次）的CsA进行治疗。对照组包括未用CsA治疗的同种异体移植物和同基因移植物。30天后，收获气管并进行组织学检查。CsA显著减少了同种异体移植物中纤维组织增生的发生（治疗组同种异体移植物中为19%，未治疗组为90%，P<0.0001），但并未减少炎症或气道上皮细胞损伤。高剂量（25mg/kg/天）CsA在减少纤维组织增生方面比低剂量更有效（高剂量组为0%，低剂量组为29%，P=0.04）。这些发现表明CsA显著减少了OB病理病变的发生，并支持了同种免疫在该疾病发病机制中的作用。
