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Downregulation of lysyl oxidase and upregulation of cellular thiols in rat fetal lung fibroblasts treated with cigarette smoke condensate
- Source :
- Toxicological sciences : an official journal of the Society of Toxicology. 83(2)
- Publication Year :
- 2004
-
Abstract
- Lysyl oxidase (LO), a copper-dependent enzyme, plays a critical role in the formation and repair of the extracellular matrix (ECM) by catalyzing the crosslinking of elastin and collagen. To better understand mechanisms of cigarette smoke (CS)-induced emphysema, we examined changes in LO and its substrates, i.e., elastin and collagen type I, the major components of cellular thiols, i.e., metallothionein (MT) and glutathione (GSH), and gamma-glutamylcysteine synthetase (gamma-GCS), a key enzyme for GSH biosynthesis, in cigarette smoke condensate (CSC)-treated rat fetal lung fibroblasts (RFL6). Exposure of RFL6 cells to CSC decreased levels of LO catalytic activity, mRNA, and protein, i.e., the 46 kDa preproenzyme, the 50 kDa proenzyme and the 32 kDa mature enzyme in a dose-dependent manner. In addition, CSC also inhibited the expression of collagen type I and elastin, substrates of LO and important components of the lung ECM. Meanwhile, cellular thiols including MT and GSH as well as gamma-GCS were markedly upregulated in CSC-treated cells. To evaluate modulation of LO expression by cellular thiols, we further examined the effect of increased levels of GSH on LO expression at protein and catalytic levels. Interestingly, exposure of cells to glutathione monoethyl ester, a GSH delivery system, effectively elevated cellular GSH levels and induced a dose-dependent decrease in levels of the protein species and catalytic activity of LO. These results suggest that upregulation by CSC of cellular thiols may play an important role in the downregulation of LO and subsequently destabilization of the lung ECM in CS-induced emphysema.
- Subjects :
- Down-Regulation
Gene Expression
Lysyl oxidase
Toxicology
Collagen Type I
Cell Line
Extracellular matrix
Protein-Lysine 6-Oxidase
Rats, Sprague-Dawley
chemistry.chemical_compound
Fetus
Downregulation and upregulation
Smoke
Tobacco
medicine
Animals
RNA, Messenger
Sulfhydryl Compounds
Fibroblast
Lung
chemistry.chemical_classification
biology
Dose-Response Relationship, Drug
Glutathione
Fibroblasts
Aminoacyltransferases
Molecular biology
Elastin
Rats
Up-Regulation
Enzyme
medicine.anatomical_structure
chemistry
Cell culture
biology.protein
Metallothionein
Tobacco Smoke Pollution
Subjects
Details
- ISSN :
- 10966080
- Volume :
- 83
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Accession number :
- edsair.doi.dedup.....776de865ee985ff5dd8928a953b0eae5