ToxSci Advance Access published online on January 23, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj112
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1 Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
* To whom correspondence should be addressed. Copper (Cu)-dependent lysyl oxidase (LO) catalyzes crosslinking of collagen and elastin stabilizing the extracellular matrix (ECM). Chronic inhalation of cadmium (Cd), a toxic metal, induces emphysema. To probe mechanisms of Cd injury to the lung, we developed Cd-resistant (CdR) cells from rat fetal lung fibroblasts (RFL6) by chronic exposure to CdCl2 from 1 to 40 µM and further examined their expressions of LO, LO substrates and Cu scavenging thiols. Levels of cellular thiols, metallothionein and glutathione, in CdR cells were elevated to 13.0- and 3.2-fold of parental controls, respectively, whereas LO mRNA and protein levels were markedly reduced in these cells with catalytic activity declining to only 16% of the parental control. A conspicuous 52 kDa species rather then the normal 50 kDa proenzyme appeared in the CdR cell extract but not in the conditioned medium, which was codistributed with the endoplasmic reticulum marker [DiOC5(3)] within the cell, implying the Cd-induced 52 kDa species as a product of abnormal LO processing defect in secretion. Addition of Cu into CdR cell cultures enhanced the expression of LO mRNA, protein and catalytic activities reflecting limitation of Cu bioavailability for LO in these cells. With inhibition of LO, CdR cells also displayed downregulation of collagen and elastin, substrates of LO. Restoration of collagen synthesis by exposure of CdR cells to purified LO or Cu suggest that inhibition of LO and limitation of Cu cofactor by Cd as key phenotype changes accelerated collagen and elastin damage, a critical event pertinent to emphysema pathogenesis.
Received September 27, 2005
Accepted January 14, 2006
Respiratory Toxicology
Inhibition of the Expression of Lysyl Oxidase and Its Substrates in Cadmium-Resistant Rat Fetal Lung Fibroblasts
Yinzhi Zhao 1,
Song Gao 1,
Iih-Nan Chou 2,
Paul Toselli 1,
Phillip Stone 1,
and
Wande Li 1 *
2 Departments of Biochemistry and Microbiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
Wande Li, E-mail: wandeli{at}bu.edu
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