The critical role of the cellular thiol homeostasis in cadmium perturbation of the lung extracellular matrix |
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| Authors: | Yinzhi Zhao Lijun Chen Song Gao Paul Toselli Phillip Stone Wande Li |
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| Institution: | 1. Service d’ophtalmologie, université Paris-Sud, hôpital Bicêtre, AP–HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France;2. UMR 3296 CNRS, laboratoire de virologie moléculaire et structurale, bâtiment 14B, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France;3. Centre national d’ophtalmologie des Quinze-Vingts, 28, rue de Charenton, 75012 Paris, France;4. Inserm UMRS 968, institut de la vision, 17, rue Moreau, 75012 Paris, France;1. Biology Deparment, American University of Beirut, Beirut 1107 2020, Lebanon;2. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;3. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;4. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia;1. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China;2. Department of Nutrition and Food Hygiene, School of Public Health, West China Medical School, Sichuan University, Chengdu, China;3. Department of Pulmonary Tumor Ward, Sichuan Cancer Hospital, Chengdu, China;4. Peritoneal Cancer Surgery, Beijing Millennium Monument Hospital, Capital Medical University, Beijing, China;1. Univ. Lille, EA 4483 ? IMPECS ? IMPact of Environmental ChemicalS on human health, F-59000 Lille, France;2. CHU Lille, Pôle de Santé Publique, F-59000 Lille, France;3. Institut Pasteur de Lille, F-59000 Lille, France;4. Univ. Lille, Centre Universitaire de Mesures et d’Analyses, F-59000 Lille, France;5. CHU Lille, Laboratoire de Toxicologie et Génopathies, F-59000 Lille, France |
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| Abstract: | Cadmium (Cd) inhalation can result in emphysema. Cd exposure of rat lung fibroblasts (RFL6) enhanced levels of metal scavenging thiols, e.g., metallothionein (MT) and glutathione (GSH), and the heavy chain of γ-glutamylcysteine synthetase (γ-GCS), a key enzyme for GSH biosynthesis, concomitant with downregulation of lysyl oxidase (LO), a copper-dependent enzyme for crosslinking collagen and elastin in the extracellular matrix (ECM). Cd downregulation of LO in treated cells was closely accompanied by suppression of synthesis of collagen, a major structure component of the lung ECM. Using rats intratracheally instilled with cadmium chloride (30 μg, once a week) as an animal model, we further demonstrated that although 2-week Cd instillation induced a non-significant change in the lung LO activity and collagen synthesis, 4- and 6-week Cd instillation resulted in a steady decrease in the lung LO and collagen expression. The lung MT and total GSH levels were both upregulated upon the long-term Cd exposure. Emphysematous lesions were generated in lungs of 6-week Cd-dosed rats. Increases of cellular thiols by transfection of cells with MT-II expression vectors or treatment of cells with GSH monoethyl ester, a GSH delivery system, markedly inhibited LO mRNA levels and catalytic activities in the cell model. Thus, Cd upregulation of cellular thiols may be a critical cellular event facilitating downregulation of LO, a potential mechanism for Cd-induced emphysema. |
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