Role of oxidative stress and mitophagy in the development of amiodarone-induced pulmonary fibrosis

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VenkatesanShalini_2017_04_05.pdf (10.18 MB)

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2016

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DOI:
http://dx.doi.org/10.22029/jlupub-14406

Abstract

Amiodarone (AD) is a bi-iodinated benzofuran derivative, classified as Class III anti-arrhythmic drug. Despite its therapeutic potential, AD inflicts several cardiac and extra-cardiac side effects. Being a cationic amphiphilic drug, AD exhibits high lipophilicity. This aids in the accumulation of the drug and its metabolite, N-desethylamiodarone (DEA) in high lipid containing organs viz adipose tissue, thyroid, liver, lungs and so on, thereby causing potentially harmful off-target effects. Although AD mediated thyroid and ophthalmic effects are more prevalent, AD-induced pulmonary toxicity (AIPT) is often fatal. Severe pulmonary toxicity has been reported in patients receiving even low doses of AD. Pulmonary fibrosis is one of the most frequently reported manifestations of AIPT. Although the precise molecular mechanism underlying AIPT still remains obscure, interplay between several direct and indirect mechanisms such as cytotoxic insult, immune mediated inflammatory process and angiotensin system activation might contribute towards the development of AIPT. Direct exposure to AD has been shown to induce apoptosis in various mammalian lung cell types including the human alveolar epithelial cells (AECs) in vitro. Apoptosis of alveolar epithelial cells (AECII) has been suggested to be a prime factor driving the development of pulmonary fibrosis.Collectively, the present study demonstrates that a) AD-induced AECII apoptosis is LC3B dependent and thus AD-induced macroautophagy is anti-survival in AECII b) AD increases oxidative stress and drives aberrant mitophagy via p62 resulting in AECII apoptosis c) AD-induced autophagy is HO-1 independent.

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