Relationship of fiber surface iron and active oxygen species to expression of procollagen, PDGF-A, and TGF-beta(1) in tracheal explants exposed to amosite asbestos

Am J Respir Cell Mol Biol. 2001 Apr;24(4):427-35. doi: 10.1165/ajrcmb.24.4.4225.

Abstract

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)-beta(1). Neither asbestos alone nor iron-loaded asbestos affected gene expression of PDGF-B, tumor necrosis factor-alpha, or TGF-alpha. The AOS scavenger tetramethylthiourea or treatment of fibers with the iron chelator deferoxamine prevented asbestos-induced increases in procollagen, PDGF-A, and TGF-beta 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-beta(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 kappa B activation. Surface iron and AOS also play a role in PDGF-A and TGF-beta gene expression, but through an ERK-dependent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asbestos, Amosite / toxicity*
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression / drug effects
  • Iron / pharmacology*
  • Leupeptins / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Male
  • NF-kappa B / metabolism
  • Platelet-Derived Growth Factor / genetics*
  • Procollagen / genetics*
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Trachea / cytology
  • Trachea / metabolism*
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • Leupeptins
  • NF-kappa B
  • Platelet-Derived Growth Factor
  • Procollagen
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • platelet-derived growth factor A
  • Asbestos, Amosite
  • Iron
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one