Adams B F, Berry G J, Huang X, Shorthouse R, Brazelton T, Morris R E
Department of Cardiothoracic Surgery, Stanford University School of Medicine, California 94305-5407, USA.
Transplantation. 2000 Jun 15;69(11):2260-6. doi: 10.1097/00007890-200006150-00007.
Obliterative bronchiolitis remains a major long-term complication after lung transplantation. Using a reproducible model of heterotopically transplanted rat tracheas, this study examined the role of several novel immunosuppresive compounds to prevent and reverse obliterative airway disease in these animals.
Brown Norway rat trachea were transplanted into the greater omentum of Lewis (allografts) or Brown Norway (isografts) animals. Recipient animals were treated with rapamycin, cyclosporine, 15-deoxyspergulin, mycophenolate mofetil, or leflunomide from day 0, 7, or 14 until day of graft removal, either day 28 or 50. Trachea segments were evaluated for degree of lumenal occlusion, as well as percent and type of lumen epithelial cell coverage.
All untreated allografted tracheas obliterated completely, although isografts appeared patent with normal respiratory epithelium when they were removed. Leflunomide, rapamycin, and cyclosporine effectively prevented obliteration when treatment was initiated at day 0, with rapamycin showing continued efficacy when initiated as late as day 7. 15-deoxyspergulin and mycophenolate mofetil failed to consistently inhibit obliteration with any treatment schedule. An inverse correlation was found between epithelial coverage and degree of obliteration, and was especially pronounced in grafts from cyclosporine-treated animals.
Immunosuppressive drug therapy will inhibit airway obliteration, but efficacy sharply diminishes if initiation of treatment is delayed. Efficacy also varies among immunosuppressive compounds, and results indicate those drugs that enable epithelial regrowth most effectively inhibit airway graft obliteration.
闭塞性细支气管炎仍然是肺移植后的主要长期并发症。本研究使用可重复的大鼠异位移植气管模型，检测了几种新型免疫抑制化合物在预防和逆转这些动物闭塞性气道疾病中的作用。
将棕色挪威大鼠的气管移植到Lewis大鼠（同种异体移植）或棕色挪威大鼠（同基因移植）的大网膜中。从第0天、第7天或第14天开始，给受体动物使用雷帕霉素、环孢素、15-脱氧精胍菌素、霉酚酸酯或来氟米特，直至移植气管切除日（第28天或第50天）。评估气管段的管腔闭塞程度，以及管腔上皮细胞覆盖的百分比和类型。
所有未治疗的同种异体移植气管均完全闭塞，而异基因移植气管在切除时外观正常，呼吸上皮完整。当在第0天开始治疗时，来氟米特、雷帕霉素和环孢素可有效预防闭塞，雷帕霉素即使在第7天开始使用也持续有效。15-脱氧精胍菌素和霉酚酸酯在任何治疗方案下均未能持续抑制闭塞。上皮覆盖与闭塞程度呈负相关，在环孢素治疗的动物移植气管中尤为明显。
免疫抑制药物治疗可抑制气道闭塞，但如果治疗开始延迟，疗效会急剧下降。免疫抑制化合物的疗效也各不相同，结果表明，那些能最有效地促进上皮再生的药物对气道移植闭塞的抑制作用最强。
