Pulmonary Responses to Amiodarone in Hamsters: Comparison of Intratracheal and Oral Administrations
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文摘
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 an 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.