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

Abstract

Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous adverse effects, including potentially lifethreatening pulmonary fibrosis. The current study was undertaken to investigate potential protective mechanisms of vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three weeks after intratracheal administration of AM (1.83 mol), increased pulmonary hydroxyproline content and histological damage were observed, indicative of fibrosis. These effects were preceded by increased pulmonary levels of transforming growth factor (TGF)-␤ 1 mRNA at 1 week post-AM, which remained elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in rapid pulmonary accumulation of the vitamin, and prevention of AM-induced increases in TGF-␤ 1 , hydroxyproline, and histological damage. Although dietary supplementation also markedly elevated lung mitochondrial vitamin E content, it did not attenuate AM-induced inhibition of mitochondrial respiration or disruption of mitochondrial membrane potential in vitro, or lung mitochondrial respiratory inhibition resulting from in vivo AM administration. These results suggest that vitamin E reduces the extent of pulmonary damage after AM administration via downregulating TGF-␤ 1 overexpression but that it does not modify AM-induced mitochondrial dysfunction, a potential initiating event in AIPT.Pulmonary toxicity is an adverse effect of great concern in patients on amiodarone (AM) pharmacotherapy (Pollak, 1999). This is primarily due to the potential for development of pulmonary fibrosis, a condition for which there is currently no effective treatment and for which patient prognosis is poor (Phan, 1995). The pathogenesis of AM-induced pulmonary toxicity (AIPT) has not been elucidated and may involve numerous processes (Massey et al., 1995;Reasor and Kacew, 1996). Several in vitro studies have demonstrated deleterious effects of AM on mitochondrial structure and function (Fromenty et al., 1990;Yasuda et al., 1996;Card et al., 1998).Furthermore, AM and its primary metabolite N-desethylamiodarone (DEA) cause disruption of mitochondrial membrane potential and decrease cellular ATP levels before cell death in freshly isolated hamster lung cells, with DEA being more potent than AM (Bolt et al., 2001a). Thus, mitochondrial dysfunction induced by AM and DEA may be critical to initiation of AM pulmonary cytotoxicity that precedes fibrosis.Vitamin E has been reported to decrease AM-induced cytotoxicity in cultured pulmonary (Futamura, 1996) and nonpulmonary cells (Kachel et al., 1990;Ruch et al., 1991), whereas other antioxidant treatments were ineffective. Additionally, cell type-selective protection against AM-induced cytotoxicity by vitamin E in isolated hamster lung cells has been observed (Bolt et al., 2001b). In the in vivo hamster model of AIPT, we showed that dietary vitamin E supplementation substantially reduced the extent of pulmonary collagen deposition and histological damage after intratracheal AM administration (Card et al., 1...

The Preventive Role of Gemfibrozil on Bleomycin-Induced Lung Injury and Fibrosis in Rats

“…The protective mechanisms of vitamin E against amiodaroneinduced pulmonary toxicity has been shown. Results have shown that vitamin E administration decreases the high level of TGF-β1 and hydroxyproline, which leads to reversal tissue destruction (33). In relation to antioxidant effects, the past results are similar to the current study.…”

“…It was shown that changes of collagen are a clear indication of fibrosis (29)(30)(31). The models of BLM or amiodarone-induced pulmonary fibrosis have determined increased hydroxyproline, which represents the destruction of tissue (32,33). The current results confirmed the useful effect of GEM on pulmonary damage and fibrosis and it was clear that GEM at a dose of 100 mg/kg had a greater effect.…”

The TGF-β Pathway as an Emerging Target for Chagas Disease Therapy

“…However, amiodarone is known to induce fibrosis in the lung in preclinical models via an increase in TGF-β1 and in collagen I expression. 73 Vitamin E attenuates amiodarone-induced pulmonary fibrosis while suppressing TGF-β1 expression. 73 A recent in vitro study showed that amiodarone promotes heart-cell recovery and gap-junction reconfiguration.…”

“…73 Vitamin E attenuates amiodarone-induced pulmonary fibrosis while suppressing TGF-β1 expression. 73 A recent in vitro study showed that amiodarone promotes heart-cell recovery and gap-junction reconfiguration. 74 These data stress the need for further retrospective and prospective studies on the effects of amiodarone on patients with Chagas disease that would take into account their genetic polymorphism in the TGFB1 gene and their possibly correlated circulating TGF-β1 levels.…”

Antioxidants as Potential Therapeutics for Lung Fibrosis

“…PBN has been shown to directly scavenge the aryl radical produced by amiodarone (146). 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).…”