ToxSci Advance Access originally published online on October 27, 2004
Toxicological Sciences 2005 83(2):372-379; doi:10.1093/toxsci/kfi019
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Toxicological Sciences vol. 83 no. 2 © Society of Toxicology 2005; all rights reserved.
Downregulation of Lysyl Oxidase and Upregulation of Cellular Thiols in Rat Fetal Lung Fibroblasts Treated with Cigarette Smoke Condensate
* Departments of Biochemistry and Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
Received July 26, 2004; accepted October 16, 2004
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 (
-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 -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.
Key Words: cigarette smoke condensate; lysyl oxidase; glutathione; metallothionein; collagen type I; elastin.
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