Therapeutic effects of α-lipoic acid on bleomycin-induced pulmonary fibrosis in rats

Abstract

Abstract. Pulmonary fibrosis (PF) is a major side effect of radiotherapy and chemotherapy. Recent clinical trials, unfortunately, have failed to identify any therapeutic agent which has the potential to reduce the consequences of this devastating condition. Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of PF. We investigated these factors to determine the protective effects of antioxidant α-lipoic acid (LA) against antineoplastic agent bleomycin (BLM)-induced oxidant lung toxicity in Sprague-Dawley rats. At different time intervals after BLM administration, pathological changes of the lung were analyzed with the measurement of total protein in bronchoalveolar lavage fluid (BALF), hydroxyproline (HYP) content and the level of three oxidative stress markers, i.e. malondialdehyde (MDA), the GSH/GSSG ratio, and total antioxidative capability (T-AOC). Also, the expression changes of MMP-1 and TIMP-1 were measured. At day 14 or 28 after BLM administration, protein content in BALF, and HYP, MDA and T-AOC contents of the lung increased significantly with a decreased GSH/GSSG ratio, implicating an increased efflux of GSSG from the lung and consumption of GSH. In contrast, treatment with LA protected BLM-induced pulmonary injury by suppressing oxidative stress with the reduction of MDA, and the enhancement of the GSH/GSSG ratio and T-AOC. The BLM-stimulated symptoms of PF were relieved with significant reduction of HYP and total proteins in LA-treated rats. LA also ameliorated the MMP-1/TIMP-1 ratio. These results suggest that LA inhibits BLM-induced lung toxicity associated with oxidative damage. Therefore, antioxidant LA has a potential therapeutic effect in the prevention and alleviation of PF.

Protection of bleomycin-induced fibrosis and inflammation by taurine

“…Bleomycin exposure was also associated with a significant increase in hydroxyproline levels in lung lavage fluids [23,24]. However, pretreatment of the rats with taurine significantly decreased the hydroxyproline levels at 7 days post bleomycin.…”

“…Hydroxyproline and taurine were measured by a modified sensitive reverse-phase HPLC assay [22][23][24]. Hydroxyproline and taurine standard solutions were used to generate standard curves.…”

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“…Alphalipoic acid was found to improve the levels of antioxidants in BLM induced rats 52. Boswellic acid 53 supplementation on BLM induction was found to improve the levels of GSH in the lung tissue.…”

“…Glutathione (GSH), an intracellular thiol acts as a nonenzymatic antioxidant and provides a protection to the lung from oxidative damage imposed by endogenous or exogenous lung toxicants 51,52 . However, its depletion in the lung by a fibrogenic agent, such as BLM as shown in the present study may be associated with the risk of lung damage 35, 51. Co-administration of PGAE with BLM reversed GSH depletion and subsequent lung damage.…”

Cytoprotective Effect of Alpha-Lipoic Acid on Paraquat-Exposed Human Bronchial Epithelial Cells <i>via</i> Activation of Nuclear Factor Erythroid Related Factor-2 Pathway

“…19,20) LA has multiple pharmacological effects that are able to ameliorate lung injury. 21,22) All these features support the potential of LA as a candidate compound to alleviate oxidative stress. However, the efficacy of LA in PQ-induced oxidative toxicity in human bronchial epithelial cells is unknown.…”