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Induction of c-jun and TGF-beta 1 in Fischer 344 rats during amiodarone-induced pulmonary fibrosis
W H Chung1, B M Bennett, W J Racz
1Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Abstract:
Amiodarone (AM) is an antidysrhythmic agent with a propensity to cause pulmonary toxicity, including potentially fatal fibrosis. In the present study, the potential roles of c-Jun and transforming growth factor (TGF)-beta 1 in AM-induced inflammation and fibrogenesis were examined after intratracheal administration of AM (1.83 micromol/day on days 0 and 2) or an equivalent volume (0.4 ml) of distilled water to male Fischer 344 rats. Northern and immunoblot analyses demonstrated that lung TGF-beta 1 (mRNA and protein) expression was increased 1.5- to 1.8-fold relative to control during the early inflammation period and 1 day, 1 wk, and 2 wk post-AM treatment. Lung c-Jun protein expression was increased concomitantly with evidence of AM-induced fibrosis; at 5 wk post-AM treatment, c-Jun protein was increased 3.3-fold relative to control. The results indicate a role for induction of c-jun and TGF-beta 1 expression in the development of AM-induced pulmonary fibrosis in the Fischer 344 rat and provide potential targets for therapeutic intervention.
Insights
Amiodarone-induced lung fibrosis in rats involves increased expression of TGF-beta 1 and c-Jun. These findings suggest potential therapeutic targets for preventing amiodarone pulmonary toxicity.
Area of Science:
- Pulmonary Medicine
- Toxicology
- Molecular Biology
Background:
- Amiodarone (AM) is an antidysrhythmic drug known to cause pulmonary toxicity, including potentially fatal fibrosis.
- The molecular mechanisms underlying amiodarone-induced lung fibrosis are not fully understood.
Purpose of the Study:
- To investigate the roles of c-Jun and transforming growth factor (TGF)-beta 1 in amiodarone-induced pulmonary inflammation and fibrogenesis.
- To explore potential therapeutic targets for amiodarone pulmonary toxicity.
Main Methods:
- Male Fischer 344 rats received intratracheal administration of amiodarone (AM) or distilled water.
- Lung tissue was analyzed using Northern and immunoblot analyses to assess TGF-beta 1 and c-Jun expression (mRNA and protein).
Main Results:
- Lung TGF-beta 1 (mRNA and protein) expression increased 1.5- to 1.8-fold during early inflammation and at 1 day, 1 week, and 2 weeks post-AM treatment.
- Lung c-Jun protein expression increased 3.3-fold at 5 weeks post-AM treatment, coinciding with observed fibrosis.
- Increased TGF-beta 1 and c-Jun expression correlated with amiodarone-induced pulmonary changes.
Conclusions:
- The induction of c-Jun and TGF-beta 1 expression plays a significant role in the development of amiodarone-induced pulmonary fibrosis in rats.
- Targeting c-Jun and TGF-beta 1 pathways may offer therapeutic strategies for mitigating amiodarone pulmonary toxicity.
