Blake T L, Reasor M J
Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown 26506-9223, USA.
Toxicol Appl Pharmacol. 1995 Apr;131(2):325-31. doi: 10.1006/taap.1995.1075.
Amiodarone (AD) has been shown to produce a transient pulmonary fibrosis in hamsters after intratracheal (i.t.) instillation. The goal of this study was to examine bronchoalveolar lavage (BAL) parameters during the development of fibrosis after i.t. AD in hamsters and to examine the responses to oral AD in hamsters for comparison to responses to i.t. AD in an effort to explore the roles of inflammation, phospholipidosis, and lung drug burden in AD-induced pulmonary disease. Two i.t. instillations on Days 0 and 7 of AD in hamsters produced fibrosis as characterized by elevated lung hydroxyproline content and variable increases in lavage macrophage, neutrophil, and eosinophil number through Day 28. Intratracheal AD also increased the permeability of the alveolar-capillary barrier as evidenced by an increase in BAL fluid albumin only on Day 8. Pulmonary phospholipidosis was not induced by i.t. AD and only small amounts of AD and its metabolite desethyl-AD (dAD) were detected in lung tissue through Day 10 after instillation on Days 0 and 7. The repeated oral administration of AD did not result in pulmonary fibrosis during the 35-day course of this study. Oral AD did cause a sustained increase in BAL fluid neutrophil number; other BAL cells were only slightly affected. Oral AD did not increase BAL fluid albumin content but a prominent BAL cell phospholipidosis was noted. Measurement of AD and dAD in lung tissue demonstrated a substantial accumulation of drug and metabolite after oral treatment with AD. The results of this study indicate that lung drug burden, pulmonary phospholipidosis, and lung neutrophil influx are not crucial factors in the development of AD-induced pulmonary fibrosis in hamsters. This study supports the possible involvement of physical damage to the lung and/or pulmonary eosinophilia in the generation of AD-induced pulmonary fibrosis in hamsters.
胺碘酮（AD）经气管内（i.t.）注入仓鼠后，已被证明会产生短暂性肺纤维化。本研究的目的是检查仓鼠经i.t.注入AD后纤维化发展过程中的支气管肺泡灌洗（BAL）参数，并检查仓鼠口服AD后的反应，以便与i.t.注入AD后的反应进行比较，从而探索炎症、磷脂沉积症和肺药物负荷在AD诱导的肺部疾病中的作用。在仓鼠第0天和第7天进行两次i.t.注入AD后，可产生纤维化，其特征为肺羟脯氨酸含量升高，且在第28天前灌洗巨噬细胞、中性粒细胞和嗜酸性粒细胞数量有不同程度增加。气管内注入AD还增加了肺泡 - 毛细血管屏障的通透性，仅在第8天BAL液白蛋白增加可证明这一点。气管内注入AD未诱导肺磷脂沉积症，在第0天和第7天注入后第10天，肺组织中仅检测到少量的AD及其代谢物去乙基AD（dAD）。在本研究的35天过程中，重复口服AD未导致肺纤维化。口服AD确实导致BAL液中性粒细胞数量持续增加；其他BAL细胞仅受到轻微影响。口服AD未增加BAL液白蛋白含量，但观察到明显的BAL细胞磷脂沉积症。肺组织中AD和dAD的测量表明，口服AD治疗后药物和代谢物大量蓄积。本研究结果表明，肺药物负荷、肺磷脂沉积症和肺中性粒细胞流入不是仓鼠中AD诱导的肺纤维化发展的关键因素。本研究支持肺物理损伤和/或肺嗜酸性粒细胞增多可能参与仓鼠中AD诱导的肺纤维化的发生。
