Document Detail

The critical role of the cellular thiol homeostasis in cadmium perturbation of the lung extracellular matrix.
MedLine Citation:
PMID:  19879314     Owner:  NLM     Status:  MEDLINE    
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 gamma-glutamylcysteine synthetase (gamma-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 microg, 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.
Yinzhi Zhao; Lijun Chen; Song Gao; Paul Toselli; Phillip Stone; Wande Li
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-10-29
Journal Detail:
Title:  Toxicology     Volume:  267     ISSN:  1879-3185     ISO Abbreviation:  Toxicology     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-02-01     Completed Date:  2010-02-26     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  60-9     Citation Subset:  IM    
Copyright Information:
2009 Elsevier Ireland Ltd. All rights reserved.
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MeSH Terms
Cadmium / toxicity*
Cell Line
Collagen / biosynthesis
Disease Models, Animal
Emphysema / chemically induced,  metabolism,  pathology
Extracellular Matrix / drug effects,  metabolism*
Gene Expression Regulation, Enzymologic / drug effects
Glutamate-Cysteine Ligase / genetics,  metabolism
Glutathione / metabolism
Homeostasis / drug effects
Lung / drug effects,  enzymology,  metabolism*
Metallothionein / genetics,  metabolism
Protein-Lysine 6-Oxidase / genetics,  metabolism
RNA, Messenger / metabolism
Rats, Sprague-Dawley
Sulfhydryl Compounds / metabolism*
Grant Support
2 R56-ES 011340/ES/NIEHS NIH HHS; R01 ES011340/ES/NIEHS NIH HHS; R01 ES011340-06A2/ES/NIEHS NIH HHS; R01-ES 011340/ES/NIEHS NIH HHS; R56 ES011340/ES/NIEHS NIH HHS; R56 ES011340-06A1/ES/NIEHS NIH HHS
Reg. No./Substance:
0/RNA, Messenger; 0/Sulfhydryl Compounds; 00BH33GNGH/Cadmium; 9007-34-5/Collagen; 9038-94-2/Metallothionein; EC 6-Oxidase; EC Ligase; GAN16C9B8O/Glutathione

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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