Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells
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Cigarette smoke extracts (CSE) induce oxidative stress, an important feature in chronic obstructive pulmonary disease (COPD), and oxidative stress contributes to the poor clinical efficacy of corticosteroids in COPD patients. Carbocysteine, an antioxidant and mucolytic agent, is effective in reducing the severity and the rate of exacerbations in COPD patients. The effects of carbocysteine on CSE-induced oxidative stress in bronchial epithelial cells as well as the comparison of these antioxidant effects of carbocysteine with those of fluticasone propionate are unknown. The present study was aimed to assess the effects of carbocysteine (10−4 M) in cell survival and intracellular reactive oxygen species (ROS) production (by flow cytometry) as well as total glutathione (GSH), heme oxygenase-1 (HO-1), nuclear-related factor 2 (Nrf2) expression and histone deacetylase 2 (HDAC-2) expression/activation in CSE-stimulated bronchial epithelial cells (16-HBE) and to compare these effects with those of fluticasone propionate (10−8 M). CSE, carbocysteine or fluticasone propionate did not induce cell necrosis (propidium positive cells) or cell apoptosis (annexin V-positive/propidium-negative cells) in 16-HBE. CSE increased ROS production, nuclear Nrf2 and HO-1 in 16-HBE. Fluticasone propionate did not modify intracellular ROS production, GSH and HDCA-2 but reduced Nrf2 and HO-1 in CSE-stimulated 16-HBE. Carbocysteine reduced ROS production and increased GSH, HO-1, Nrf2 and HDAC-2 nuclear expression/activity in CSE-stimulated cells and was more effective than fluticasone propionate in modulating the CSE-mediated effects. In conclusion, the present study provides compelling evidences that the use of carbocysteine may be considered a promising strategy in diseases associated with corticosteroid resistance.
KeywordsCigarette smoke Airway epithelial cells Reactive oxygen species
Cigarette smoke extracts
Reactive oxygen species
Nuclear-related factor 2
Histone deacetylase 2
This work was mainly supported by the Italian National Research Council and by Dompè, Italy. Elisabetta Pace declares that she has had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis.
- Kratschmar DV, Calabrese D, Walsh J, Lister A, Birk J, Appenzeller-Herzog C, Moulin P, Goldring CE, Odermatt A (2012) Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11β-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One 7:e36774PubMedCrossRefGoogle Scholar
- Malhotra D, Thimmulappa RK, Mercado N, Ito K, Kombairaju P, Kumar S, Ma J, Feller-Kopman D, Wise R, Barnes P, Biswal S (2011) Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest 121:4289–4302PubMedCrossRefGoogle Scholar
- Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, Kilty I, Rahman I (2004) Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J 18:1897–1899PubMedGoogle Scholar
- Pace E, Bruno TF, Berenger B, Mody CH, Melis M, Ferraro M, Tipa A, Bruno A, Profita M, Bonsignore G, Gjomarkaj M (2007) Elevated expression of prostaglandin receptor and increased release of prostaglandin E2 maintain the survival of CD45RO+ T cells in the inflamed human pleural space. Immunology 121:427–436PubMedCrossRefGoogle Scholar
- Pace E, Scafidi V, Di Bona D, Siena L, Chiappara G, Ferraro M, La Grutta S, Gallina S, Speciale R, Ballacchino A, Bachert C, Bousquet J, Gjomarkaj M (2012a) Increased expression of IL-19 in the epithelium of patients with chronic rhinosinusitis and nasal polyps. Allergy 67:878–886CrossRefGoogle Scholar
- Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Chen P, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan BT, Qian HP, Zhi RC, Zhong NS (2008) Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised placebo-controlled study. Lancet 371:2013–2018PubMedCrossRefGoogle Scholar