Semester

Spring

Date of Graduation

2001

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Mark J. Reasor.

Abstract

Amiodarone (AD) is gaining support as a first-line antiarrhythmic drug despite its potentially fatal pulmonary toxicity involving inflammation and fibrosis. The goals of this study were to develop and characterize a rat model of amiodarone-induced pulmonary toxicity (AIPT). A protocol was developed in which male F344 rats were instilled intratracheally (i.t.) with AD (6.25 mg/kg with a 3.125 mg/ml solution) in sterile water or the sterile water vehicle on days 0 and 2, a protocol that led to the development of pulmonary fibrosis on day 28 in the AD-treated animals. Bronchoalveolar lavage (BAL) resulted in the increased recovery of alveolar macrophages, neutrophils, and eosinophils from i.t. AD-treated rats. The BAL cells recovered from AD-treated rats at day 3 produced more integrated phorbol-myristate-acetate stimulated luminol-dependent chemiluminescence over 20 minutes than BAL cells from control rats. These findings indicate that this model exhibits a transient pulmonary inflammation, with the potential for elevated oxidant production in the lungs, and subsequent pulmonary fibrosis. Also, serum levels of surfactant protein-D, a protein normally found in the lungs, was elevated in the serum of i.t. AD-treated rats, and is proposed as a biomarker for the toxicity. However, attempts to elucidate the cytokine signaling behind the inflammatory events were unsuccessful. It was discovered that AD instillation produces a rapid and massive damage to the alveolar-capillary barrier, and cellular death or damage to lung airway and parenchymal cells. This pathology is not consistent with that found in human AIPT. AD in solution was found to be at least partly in the form of a free radical, and capable of generating hydroxyl radicals. An attempt to modulate the toxicity of Lt. AD by incorporating water-soluble antioxidants in the drug solution was unsuccessful, and might have exacerbated the condition. No consistent evidence for deiodination of AD in solution was found, leaving the mechanism and significance of free radical generation by AD undetermined.

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