Mineral dusts directly induce epithelial and interstitial fibrogenic mediators and matrix components in the airway wall.
Exposure to mineral dusts is associated with the development of chronic airflow obstruction, probably mediated in part by dust-induced fibrosis of the small airways. To investigate the mechanism of fibrosis, we exposed rat tracheal explants to amosite asbestos, iron oxide, or titanium dioxide. Explants were then maintained in air organ culture, and the expression of genes encoding for various mediators and matrix components assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). At 7 d, all dusts produced significant increases in platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta1 (TGF-beta1) gene expression compared with control; asbestos and titanium dioxide produced increases in PDGF-B, and titanium dioxide increased TGF-alpha expression. Only asbestos caused increases in procollagen expression. No dust increased expression of tumor necrosis factor-alpha (TNF-alpha), fibronectin, or tropoelastin. Elevations in these factors coincided temporally with transport of particles into the epithelium and then to the subepithelial space. By in situ hybridization, TGF-beta gene expression was found in both the epithelium and subepithelial (interstitial) space, and PDGF-B and procollagen gene expression in the subepithelial space. Chemical analysis showed a small increase in hydroxyproline, a measure of collagen content, in asbestos-treated explants. We conclude that mineral dusts can induce airway wall fibrosis by directly upregulating proliferative and fibrogenic mediators as well as matrix components in the airway epithelium and interstitium, and that neither airspace nor circulating inflammatory cells are required for these effects. Different mineral dusts produce different patterns of reaction.
Dai
J
J
Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
Gilks
B
B
Price
K
K
Churg
A
A
D000402:Airway Obstruction / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017639:Asbestos, Amosite / Q000009:adverse effects; D046508:Culture Techniques; D004391:Dust / Q000009:adverse effects*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000187:drug effects* / Q000235:genetics; D005290:Ferric Compounds / Q000009:adverse effects; D005353:Fibronectins / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000187:drug effects / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D007509:Irritants / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019016:Mineral Fibers / Q000009:adverse effects; D008903:Minerals / Q000009:adverse effects*; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000235:genetics; D011347:Procollagen / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014025:Titanium / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics; D014333:Tropoelastin / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
D004391:Dust; D016326:Extracellular Matrix Proteins; D005290:Ferric Compounds; D005353:Fibronectins; D018836:Inflammation Mediators; D007509:Irritants; D019016:Mineral Fibers; D008903:Minerals; D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D014409:Tumor Necrosis Factor-alpha; D017639:Asbestos, Amosite; C009495:titanium dioxide; C000499:ferric oxide; D014025:Titanium; D011505:Protein-Tyrosine Kinases; D006909:Hydroxyproline