Iron loading makes a nonfibrogenic model air pollutant particle fibrogenic in rat tracheal explants.
To examine the potential role of particle iron in fibrogenicity, we loaded nonfibrogenic fine (0.12micro) TiO(2) with increasing amounts of Fe(II)-Fe(III) chloride. Dusts were applied to rat tracheal explants, which were maintained in air organ culture for 1 wk. Iron-loaded dust increased procollagen gene expression and tissue hydroxyproline. The active oxygen species (AOS) scavenger tetramethylthiourea prevented these effects. Iron loading caused nuclear factor (NF)-kappaB activation, decreased levels of total IkappaBalpha, but relatively increased levels of both IkappaBalpha-phosphoserine 32/36 and IkappaBalpha-phosphotyrosine. A citrate extract of iron-loaded dust increased procollagen expression. Gel shift using a probe consisting of the NF-kappaB consensus sequence from the prolyl-4-hydroxylase promoter and adjacent bases showed increased nuclear binding, and RT-PCR examination showed increased prolyl-hydroxylase alpha-chain gene expression after iron loading. We conclude that addition of surface iron can convert a nonreactive model air pollutant particle into a fibrogenic particle via AOS- and NF-kappaB-dependent pathways, probably through two different NF-kappaB activation pathways in two different anatomic compartments. This process may proceed in vivo through iron extracted from the dust into the cytoplasm. NF-kappaB activation may directly increase expression of prolyl hydroxylase, an enzyme involved in collagen synthesis. These findings suggest that air pollutant particles containing significant quantities of transition metals may produce airway wall fibrosis and lead to chronic obstructive pulmonary disease.
Dai
Jin
J
Department of Pathology, University of British Columbia, Vancouver, Canada.
Xie
Changshie
C
Churg
Andrew
A
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D066298:In Vitro Techniques; D007501:Iron / Q000633:toxicity*; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D000393:Air Pollutants; D017931:DNA Primers; D016328:NF-kappa B; D007501:Iron; D011393:Procollagen-Proline Dioxygenase