Induction of fibrogenic mediators by fine and ultrafine titanium dioxide in rat tracheal explants

Respirable ambient particles [particulate matter <10 micrometer (PM(10))] are associated with both acute and chronic adverse health effects including chronic airflow obstruction. PM(10) can induce expression of inflammatory and fibrogenic mediators, but there is controversy about the types and/or sizes of particles involved and, in particular, whether ultrafine particles are the major toxic agents. To examine whether particle size affects mediator generation, we exposed rat tracheal explants, an inflammatory cell-free model of the airway wall, to various concentrations up to 500 microgram/cm(2) of fine (0.12 micrometer) or ultrafine (0.021 micrometer) titanium dioxide (anatase), maintained the explants in an organ culture in air for 1-7 days, and used RT-PCR to examine the expression of fibrogenic mediators and procollagen. No increase in gene expression was seen at 1 or 3 days, but at 5 days, ultrafine dust induced a small increase in procollagen. At 7 days, fine titanium dioxide produced significantly greater increases for platelet-derived growth factor (PDGF)-B, transforming growth factor-alpha, and transforming growth factor-beta compared with those by ultrafine dust; both dusts produced similar increases for PDGF-A; and ultrafine dust produced increases in procollagen expression, whereas fine dust had no effect. Expression levels were dose related. Both dusts produced a similar decrease in expression of PDGF receptor-alpha and a similar increase in PDGF receptor-beta. These observations suggest that ultrafine particles are intrinsically able to induce procollagen expression even in the absence of inflammatory cells; that chronic exposure to PM(10) may result in chronic airflow obstruction, in part because of ultrafine particle-mediated increases in airway wall fibrosis; and that chemically identical dusts of differing size can produce quite different patterns of gene expression in the airway wall. Differential upregulation of PDGF receptors does not appear to explain dust-induced fibrosis in this model.