Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster

Abstract

Associated with amiodarone (AM) therapy is pneumonitis, which may progress to life-threatening pulmonary fibrosis. Although the etiology of amiodarone-induced pulmonary toxicity (AIPT) is unknown, a role for direct toxicity by oxidative stress has been proposed. We have used a single intratracheal administration of AM (1.8 mg (2.64 mumol)) to male golden Syrian hamsters to investigate the role of oxidative stress in AIPT. The antioxidant capacity of the lung was assessed following AM administration by evaluating glutathione status and antioxidant enzyme activities. The efficacy of treatment with the antioxidant agents butylated hydroxyanisole, diallyl sulfide, and N-acetylcysteine, in attenuation of AM-induced pulmonary fibrosis was also investigated. AM significantly (p < 0.05) increased the ratio of oxidized to total lung glutathione both 30 min (control, 0.93 +/- 0.23%; AM, 2.06 +/- 0.26%) and 120 min (control, 0.90 +/- 0.21%; AM, 3.58 +/- 1.34%) post administration. AM also increased activities of glutathione reductase (by 89%) 3 days post administration, and glutathione peroxidase (by 110 and 45%, respectively) and total superoxide dismutase (by 58 and 35%, respectively) both 3 and 7 days post administration. However, treatment of hamsters with butylated hydroxyanisole (150 mg.kg-1.day-1 s.c.) or diallyl sulfide (200 mg.kg-1.day-1, p.o.) for 3 days prior to AM, or treatment with N-acetylcysteine (10 mg intratracheally) 10 min prior to AM had no effect on pulmonary fibrosis 21 days post treatment, as determined by lung wet weight and hydroxyproline content, and had inconsistent effects on histologically determined disease index.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants as Potential Therapeutics for Lung Fibrosis

“…Vitamin E supplementation of hamsters attenuated both lung TGF-β levels and fibrosis induced by amiodarone (29,30). The thiol-based antioxidant NAC is also effective at attenuating amiodarone-induced lung fibrosis (120). In addition, the phenolic antioxidants BHA and curcumin were effective in limiting amiodarone-induced ROS and lung injury (120,152).…”

“…The thiol-based antioxidant NAC is also effective at attenuating amiodarone-induced lung fibrosis (120). In addition, the phenolic antioxidants BHA and curcumin were effective in limiting amiodarone-induced ROS and lung injury (120,152).…”

Attenuation of Amiodarone-Induced Pulmonary Fibrosis by Vitamin E Is Associated with Suppression of Transforming Growth Factor-β1Gene Expression but Not Prevention of Mitochondrial Dysfunction

“…Although a role for oxidative stress in the development of AIPT has been proposed, considerable evidence refutes the involvement of reactive oxygen species (Kachel et al, 1990;Ruch et al, 1991;Leeder et al, 1994). Nonetheless, the protective effect of vitamin E against AM toxicities in vitro and in vivo suggests a role for free radical generation in the etiology of AIPT.…”

Evaluation of reactive oxygen species involvement in amiodarone pulmonary toxicity in vivo and in vitro

“…However, there is conflicting evidence regarding the role of oxidative stress in AIPT. An established in vivo model used to study AIPT involves intratracheal AM administration to the hamster (7)(8)(9)(10). With this model, alterations in lung glutathione content (total and oxidized glutathione) were observed early after AM administration, consistent with an oxidant mechanism of toxicity (7).…”

“…An established in vivo model used to study AIPT involves intratracheal AM administration to the hamster (7)(8)(9)(10). With this model, alterations in lung glutathione content (total and oxidized glutathione) were observed early after AM administration, consistent with an oxidant mechanism of toxicity (7). Since susceptibility of the lung to oxidant stress depends on the balance of pro-oxidant and antioxidant activities, antioxidant agents have been assessed for their ability to attenuate the development of AIPT.…”