Iron Loading Makes a Nonfibrogenic Model Air Pollutant Particle Fibrogenic In Rat Tracheal Explants

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Abstract
To examine the potential role of particle iron in fibrogenicity, we loaded nonfibrogenic fine (0.12 μ ) TiO2 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)- κ B activation, decreased levels of total I κ B α, but relatively increased levels of both I κ B α -phosphoserine 32/36 and I κ B α -phosphotyrosine. A citrate extract of iron-loaded dust increased procollagen expression. Gel shift using a probe consisting of the NF- κ B consensus sequence from the prolyl-4-hydroxylase promoter and adjacent bases showed increased nuclear binding, and RT-PCR examination showed increased prolyl-hydroxylase α -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- κ B–dependent pathways, probably through two different NF- κ B activation pathways in two different anatomic compartments. This process may proceed in vivo through iron extracted from the dust into the cytoplasm. NF- κ B 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.

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