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A4752 - Selegiline Suppressed Cigarette Smoke-Induced Oxidative Stress and Inflammation Via MAO-B Inhibition in Rat Lung
Author Block: J. C. W. Mak, Y. Cui, K. W. Liu, Y. Liang, M. S. Ip; Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
Background: Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) is a rich source of oxidants and is thought to disrupt the oxidant-antioxidant balance in the lung, thus inducing inflammation. Monoamine oxidase (MAO) is a reactive oxygen species (ROS) source and may play a role in CS-induced airway oxidative stress and inflammation. The aim of this study was to explore the effect of a selective MAO-B inhibitor selegiline on CS-induced oxidative stress and inflammation in rat lung and the underlying mechanisms involved. Methods: Thirty-two male Sprague Dawley rats (5 weeks old, ~140g) were randomly divided into four groups: sham air (SA), CS, selegiline (Slg), and combination of selegiline and CS (Slg/CS). The SA and CS groups were injected with saline while the Slg and Slg/CS groups were injected daily with selegiline (2 mg/kg; i.p.). The SA and Slg groups were exposed to atmospheric air while the CS and Slg/CS groups were exposed to mainstream CS generated from the whole body inExpose smoking system (SCIREQ, Canada) for twice a day (each for 1 hour). After exposure for 7 days, rats were sacrificed to collect bronchoalveolar lavage (BAL) and lung tissues. Tissue protein was extracted for the measurement of oxidative/anti-oxidative makers and Western blots. The measurement of inflammatory mediators was carried out in BAL using ELISA. Results: CS exposure significantly increased MAO-B activity, which was attenuated by selegiline. The CS-induced elevation of MAO-B activity was in line with the significant reduction of total antioxidant capacity (T-AOC) and rGSH/GSSG ratio and elevation of elevated superoxide dismutase (SOD) and catalase (CAT) activities after CS exposure. Selegiline normalized CS-mediated alterations in enzymatic and non-enzymatic antioxidants. Selegiline suppressed CS-induced nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2), leading to attenuation of CS-mediated induction of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). In addition, selegiline reversed CS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, leading to attenuation of pro-inflammatory mediators like cytokine-induced neutrophil chemoattractant 1 (CINC-1), monocyte chemotactic protein (MCP-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in BAL.Conclusion: These findings suggest that MAO-B inhibitor selegiline may be capable of reversing CS-induced oxidative stress and inflammation via Nrf2 and NF-κB pathways. Inhibition of MAO-B may provide a promising therapeutic strategy for CS-mediated COPD.