Nicotine mediates oxidative stress and apoptosis through cross talk between NOX1 and Bcl-2 in lung epithelial cells |
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| Institution: | 1. Department of Pediatrics, Children’s Hospital, 1211 Geneva, Switzerland;2. Department of Pathology and Immunology, Medical School, and University of Geneva, Geneva, Switzerland;3. Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy;4. Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland;1. Department of Urology, Rijeka University Hospital Center, T. Stržića 3, Rijeka, Croatia;2. Department of Pathology, School of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka, Croatia;3. Ultrasound Diagnostic Service, Health Centre Rijeka, Martina Kontuša 18, 51000 Rijeka, Croatia;1. Department of Cardiology, Baylor University Hospital, Dallas, Texas;2. Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri;1. World Health Organization China Representative Office, Chaoyang District, Beijing 100600, China;1. Division of Pulmonary, Allergy, and Critical Care Medicine and the Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA 15213, USA;1. Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, 66123 Saarbrücken, Germany;2. Anatomy and Cell Biology, Medical Faculty, Saarland University, building 61, 66421 Homburg, Germany;3. University of Wuppertal, Molecular Cell Biology and Microbiology, Department of Chemistry and Biology, Gaußstr. 20, 42097 Wuppertal, Germany;4. Institute of Inorganic Chemistry – WASTe-Elemental Analysis Group, Campus C4 1, 66123 Saarbrücken, Germany |
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| Abstract: | Nicotine contributes to the onset and progression of several pulmonary diseases. Among the various pathophysiological mechanisms triggered by nicotine, oxidative stress and cell death are reported in several cell types. We found that chronic exposure to nicotine (48 h) induced NOX1-dependent oxidative stress and apoptosis in primary pulmonary cells. In murine (MLE-12) and human (BEAS-2B) lung epithelial cell lines, nicotine acted as a sensitizer to cell death and synergistically enhanced apoptosis when cells were concomitantly exposed to hyperoxia. The precise signaling pathway was investigated in MLE-12 cells in which NOX1 was abrogated by a specific inhibitor or stably silenced by shRNA. In the early phase of exposure (1 h), nicotine mediated intracellular Ca2+ fluxes and activation of protein kinase C, which in its turn activated NOX1, leading to cellular and mitochondrial oxidative stress. The latter triggered the intrinsic apoptotic machinery by modulating the expression of Bcl-2 and Bax. Overexpression of Bcl-2 completely prevented nicotine’s detrimental effects, suggesting Bcl-2 as a downstream key regulator in nicotine/NOX1-induced cell damage. These results suggest that NOX1 is a major contributor to the generation of intracellular oxidative stress induced by nicotine and might be an important molecule to target in nicotine-related lung pathologies. |
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| Keywords: | Nicotine NOX1 Bcl-2 Apoptosis Oxidative stress Alveolar epithelial type II cells Free radicals |
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