title: Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity.
abstract: Pulmonary toxicity, including fibrosis, is a serious adverse effect associated with the antidysrhythmic drug amiodarone (AM). We tested the potential usefulness of pirfenidone against AM-induced pulmonary toxicity in the hamster model. Intratracheal AM administration resulted in pulmonary fibrosis 21 days posttreatment, as evidenced by an 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)-beta1 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 after 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 able to decrease only 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-beta1 gene expression.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Card
authors.forename: William J
authors.initials: WJ
authors.lastname: Racz
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.forename: Solomon B
authors.initials: SB
authors.lastname: Margolin
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000208:Acute Disease; D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001761:Bleomycin / Q000633:toxicity; D006224:Cricetinae; D004195:Disease Models, Animal; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D000889:Anti-Arrhythmia Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C093844:pirfenidone; D000638:Amiodarone; D006909:Hydroxyproline