Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts.
Chronic inhalation of cadmium at the workplace or in cigarette smoke is associated with emphysema, a disease characterized by extensive disruption of lung connective tissue. We have previously shown that cadmium, at noncytotoxic doses, inhibits fibroblast procollagen production in vitro, with maximal inhibitory effects of 69 +/- 6% (P < 0.01) at 30 &microM cadmium chloride (CdCl2). In this paper we show that at similar doses, cadmium also inhibits proteoglycan synthesis, with values reduced by between 36 +/- 4% (P < 0.01) and 42 +/- 6% (P < 0.01) for proteoglycans secreted into the culture media and associated with the cell layer, respectively. The greatest inhibition was obtained for the major matrix-associated proteoglycans, versican, decorin, and the large heparan sulfate proteoglycans, with synthesis values reduced by between 60 and 70%. Biglycan and other heparan sulfate proteoglycans were also affected, with synthesis values reduced by between 25 and 45%. In contrast, total protein synthesis was unaffected. Furthermore, effects of cadmium at the protein level were mirrored by reduction in messenger RNA levels for alpha1(I) procollagen, versican, and decorin. These data support the hypothesis that cadmium may play an important role in the pathogenesis of emphysema associated with chronic inhalation of cadmium fumes by inhibiting the production of connective tissue proteins.
Chambers
R C
RC
Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College Medical School, Rayne Institute, London, United Kingdom. R.Chambers@ucl.ac.uk
Laurent
G J
GJ
Westergren-Thorsson
G
G
D000280:Administration, Inhalation; D002104:Cadmium / Q000633:toxicity*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism; D058575:Decorin; D003871:Dermatan Sulfate / Q000378:metabolism; D004187:Disaccharides / Q000032:analysis; D004646:Emphysema / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type; D008168:Lung / Q000187:drug effects*; D011347:Procollagen / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D053675:Versicans
D011508:Chondroitin Sulfate Proteoglycans; C546878:DCN protein, human; D058575:Decorin; D004187:Disaccharides; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011347:Procollagen; D011500:Protein Synthesis Inhibitors; D011509:Proteoglycans; D012333:RNA, Messenger; C508322:VCAN protein, human; D002104:Cadmium; D053675:Versicans; D003871:Dermatan Sulfate; D002809:Chondroitin Sulfates