Mineral Dusts Directly Induce Epithelial and Interstitial Fibrogenic Mediators and Matrix Components in the Airway Wall

Abstract

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.

Interstitial fibrosis and growth factors.

“…Rat AM secrete more PDGF (all three isoforms( following exposure to asbestos in vitro ( 134). Exposure of mineral dust to tracheal explants results in increased expression of PDGF-A and -B chain gene expression (131).…”

Influenza Virus Infection Decreases Tracheal Mucociliary Velocity and Clearance ofStreptococcus pneumoniae

“…Tracheal explant systems, such as tracheal rings or wholeorgan explants, from a variety of animal species, including hamsters, mice, rats, ferrets, pigs, guinea pigs, and chinchillas, have been widely used as an alternative to in vitro cell culture assays (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Tracheal explants have been used to investigate the effects of toxins, such as mineral dusts, air pollution particles, and cigarette smoke, on tracheal function (32,33,39).…”

“…Tracheal explants have been used to investigate the effects of toxins, such as mineral dusts, air pollution particles, and cigarette smoke, on tracheal function (32,33,39). In addition,…”

Titanium dioxide (respirable fraction) [MAK Value Documentation, 2009]

“…IL-8 is a potent "lure" for leukocytes (Standiford et al 1990). The situation is similar in the case of transforming growth factor β (TGF-β) which, in addition, stimulates the genes of collagen and fibronectin synthesis in connective tissue cells (Churg et al 1999;Dai et al 1998;Mossman and Churg 1998).…”