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ToxSci Advance Access published online on June 27, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg167
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 2, 2003; accepted June 6, 2003
© 2003 Society of Toxicology

Respiratory Toxicology

Differential Effects of Pirfenidone on Acute Pulmonary Injury and Ensuing Fibrosis in the Hamster Model of Amiodarone-Induced Pulmonary Toxicity

Jeffrey W. Card 1, William J. Racz 1, James F. Brien 1, Solomon B. Margolin 2, and Thomas E. Massey 1*

1 Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada, K7L 3N6
2 Marnac Inc., Dallas, Texas, USA, 75231

* To whom correspondence should be addressed. E-mail: masseyt{at}post.queensu.ca.


  Abstract

Pulmonary toxicity, including fibrosis, is a serious adverse effect associated with the antidysrhythmic drug amiodarone (AM). Here we have tested the potential usefulness of pirfenidone against AM-induced pulmonary toxicity in the hamster model. Intratracheal AM administration resulted in pulmonary fibrosis 21 days post-treatment, as evidenced by increased hydroxyproline content and histological damage. Dietary pirfenidone administration (0.5% w/w in chow), for 3 days prior to and continuously after AM, prevented fibrosis and suppressed elevation of pulmonary transforming growth factor (TGF)-{beta}1 mRNA content at 7 and 21 days post-AM. Protection against AM-induced lung damage was not observed when supplementation with pirfenidone was delayed until 7 days following AM administration, suggesting that alteration of early events in AM lung toxicity is necessary for the protective effect of pirfenidone. Both AM and bleomycin, another pulmonary fibrogen, caused inflammation 24 h post-intratracheal dosing, measured as increased lactate dehydrogenase activity, protein content, and cellular alterations in bronchoalveolar lavage fluid, with the response to AM markedly greater than that to bleomycin. Administration of AM, but not bleomycin, also caused whole lung mitochondrial dysfunction, alveolar macrophage death, and an influx of eosinophils into the lung, of which pirfenidone was only able to decrease the latter. We conclude that: (1) AM induces alveolar macrophage death and severe, acute pulmonary inflammation with associated eosinophilia following intratracheal administration; (2) mitochondrial dysfunction may play an early role in AM pulmonary injury; and (3) pirfenidone decreases AM-induced pulmonary fibrosis in the hamster, probably through suppression of TGF-{beta}1 gene expression.

Key Words: amiodarone, pirfenidone, lung, inflammation, fibrosis, mitochondria .


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