title: A characterization of amiodarone-induced pulmonary toxicity in F344 rats and identification of surfactant protein-D as a potential biomarker for the development of the toxicity.
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 characterize a rat model of AD-induced pulmonary toxicity (AIPT) and identify a serum biomarker to aid in the diagnosis of the onset of pulmonary toxicity. Male F344 rats were instilled intratracheally 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. Animals were killed on days 3, 5, 6, 7, or 10 and bronchoalveolar lavage (BAL) was performed. Recovery of alveolar macrophages and eosinophils was increased on days 3 and 5, while neutrophil recovery and albumin levels in the first BAL fraction were significantly elevated only on day 3. BAL cells recovered from AD-treated rats at day 3 produced more phorbol myristate acetate-stimulated luminol-dependent chemiluminescence (LDCL) over 20 min than BAL cells from control rats. Experiments using specific inhibitors implicated superoxide and nitric oxide in at least part of the LDCL response. Serum levels of surfactant protein-D (SP-D), a surfactant-associated protein, were increased concurrently with the inflammatory response in the lungs. These findings indicate that this model exhibits transient pulmonary inflammation and damage, with the potential for elevated oxidant production in the lungs and subsequent pulmonary fibrosis. Also, SP-D is proposed as a specific biomarker to monitor the onset of AIPT in this model.
authors.affiliation: Department of Pharmacology and Toxicology, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.forename: K
authors.initials: K
authors.lastname: Van Dyke
authors.forename: L L
authors.initials: LL
authors.lastname: Bowman
authors.forename: P R
authors.initials: PR
authors.lastname: Miles
authors.forename: A F
authors.initials: AF
authors.lastname: Hubbs
authors.forename: R J
authors.initials: RJ
authors.lastname: Mason
authors.forename: K
authors.initials: K
authors.lastname: Shannon
authors.forename: M J
authors.initials: MJ
authors.lastname: Reasor
mesh_terms: D000418:Albumins / Q000378:metabolism; D000638:Amiodarone / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D006023:Glycoproteins / Q000097:blood*; D006909:Hydroxyproline / Q000378:metabolism; D007442:Intubation, Intratracheal; D008163:Luminescent Measurements; D008165:Luminol; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D011658:Pulmonary Fibrosis / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants / Q000097:blood*; D051381:Rats; D011916:Rats, Inbred F344; D013047:Specific Pathogen-Free Organisms; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000418:Albumins; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D006023:Glycoproteins; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D008165:Luminol; D000638:Amiodarone; D013755:Tetradecanoylphorbol Acetate; D006909:Hydroxyproline