Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 427-435

Relationship of Fiber Surface Iron and Active Oxygen Species to Expression of Procollagen, PDGF-A, and TGF-₁ in Tracheal Explants Exposed to Amosite Asbestos

Jin Dai and Andrew Churg

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

To investigate the role of iron and active oxygen species (AOS) in asbestos-induced fibrosis, we loaded increasing amounts of Fe(II)/Fe(III) onto the surface of amosite asbestos fibers and then applied the fibers to rat tracheal explants. Explants were harvested after 7 d in air organ culture. Asbestos by itself doubled procollagen gene expression, and a further increase was seen with increasing iron loading; actual collagen content measured as hydroxyproline was increased in a similar pattern. Iron loading also increased gene expression of platelet-derived growth factor (PDGF)-A and transforming growth factor (TGF)-₁. Neither asbestos alone nor iron-loaded asbestos affected gene expression of PDGF-B, tumor necrosis factor-, or TGF-. The AOS scavenger tetramethylthiourea or treatment of fibers with the iron chelator deferoxamine prevented asbestos-induced increases in procollagen, PDGF-A, and TGF- gene expression, whereas glutathione had no effect. The proteasome inhibitor MG-132 abolished asbestos-induced increases in procollagen gene expression but did not affect increases in PDGF-A or TGF-₁ expression, whereas the extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 had exactly the opposite effect. We conclude that surface iron as well as the iron-catalyzed generation of AOS play a role in asbestos-induced matrix (procollagen) production and that this process is driven in part through oxidant-induced nuclear factor B activation. Surface iron and AOS also play a role in PDGF-A and TGF- gene expression, but through an ERK-dependent mechanism.

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