Bronchiolitis obliterans induced by intratracheal papaverine: A novel animal model
Bronchiolitis obliterans induced by intratracheal papaverine: A novel animal model
复制标题
DOI：
10.1007/s00408-003-1049-3
复制
发表时间：
2004-03-01
期刊：
影响因子：
5
通讯作者：
Herndon, B
中科院分区：
文献类型：
--
作者：
Svetlecic, J;Molteni, A;Herndon, B
缩窄性闭塞性细支气管炎（CBO）是一种毒性暴露和肺移植后出现的高度致死性综合征，目前需要对其机制进行研究。本报告建立了毒性诱导CBO的动物模型，验证了其病理学，并提出了其起源的生理机制。罂粟碱是蜥脚类植物中的生物碱，负责人体毒物诱导的CBO，用于创建大鼠模型。微渗透泵气管内输送罂粟碱长达28天（0.25毫升/小时，总计6.4毫克）。测定支气管肺泡灌洗量（BAL）。肺组织评估CBO的征象（H&E和三色染色）。还测量了人CBO中细胞因子失调（tgf - β和eNOS）。在罂粟碱治疗的动物中，早在第7天就观察到支气管周围炎症，支气管粘膜广泛剥脱和破坏，以及支气管周围胶原蛋白增加（均为CBO的典型症状），28天后损伤更广泛。肺匀浆中tgf - β和eNOS显著升高。我们通过一种新的气管内罂粟碱给药方法建立的CBO中毒模型准确地再现了人CBO的病理和细胞因子特征。罂粟碱有可能通过多种途径产生CBO。该模型为理解和发展CBO的创新治疗方法提供了一种工具。
Constrictive bronchiolitis obliterans (CBO), a highly fatal syndrome seen following toxicant exposure and lung transplantation, is in need of mechanistic study. This report creates an animal model of toxicant induced CBO, validates its pathology and suggests a physiologic mechanism for its origin. Papaverine, the alkaloid in Sauropus plants and responsible for human toxicant-induced CBO, was used to create the rat model. A mini-osmotic pump delivered papaverine intratracheally for up to 28 days (0.25 muL/hr, totaling 6.4 mg). Bronchoalveolar lavage (BAL) was measured. Lung tissue was evaluated for signs of CBO (H&E and Trichrome staining). Cytokines deregulated in human CBO were also measured (TGF-beta and eNOS). Peribronchial inflammation, extensive denudation and destruction of bronchial mucosa, as well as increased peribronchial collagen (all classic signs of CBO) were observed as early as 7 days in papaverine treated animals, with more extensive damage after 28 days. Significant elevations of TGF-beta and eNOS were seen in lung homogenates. Our toxicant induced model of CBO via a novel delivery method of intratracheal papaverine accurately reproduces pathology and cytokine profiles of human CBO. Papaverine has potential for producing CBO by multiple routes. This model introduces a vehicle for both understanding and development of innovative treatment for CBO.