title: Diminished injury in hypotransferrinemic mice after exposure to a metal-rich particle.
abstract: Using the hypotransferrinemic (Hp) mouse model, we studied the effect of altered iron homeostasis on the defense of the lung against a catalytically active metal. The homozygotic (hpx/hpx) Hp mice had greatly diminished concentrations of both serum and lavage fluid transferrin relative to wild-type mice and heterozygotes. Fifty micrograms of a particle containing abundant concentrations of metals (a residual oil fly ash) was instilled into wild-type mice and heterozygotic and homozygotic Hp animals. There was an oxidative stress associated with particle exposure as manifested by decreased lavage fluid concentrations of ascorbate. However, rather than an increase in lung injury, diminished transferrin concentrations in homozygotic Hp mice were associated with decreased indexes of damage, including concentrations of relevant cytokines, inflammatory cell influx, lavage fluid protein, and lavage fluid lactate dehydrogenase. Comparable to other organs in the homozygotic Hp mouse, siderosis of the lung was evident, with elevated concentrations of lavage fluid and tissue iron. Consequent to these increased concentrations of iron, proteins to store and transport iron, ferritin, and lactoferrin, respectively, were increased when assayed by immunoprecipitation and immunohistochemistry. We conclude that the lack of transferrin in Hp mice did not predispose the animals to lung injury after exposure to a particle abundant in metals. Rather, these mice demonstrated a diminished injury that was associated with an increase in the metal storage and transport proteins.
authors.affiliation: National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. ghio.andy@epa.gov
authors.forename: A J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: J D
authors.initials: JD
authors.lastname: Carter
authors.forename: J H
authors.initials: JH
authors.lastname: Richards
authors.forename: K M
authors.initials: KM
authors.lastname: Crissman
authors.forename: H H
authors.initials: HH
authors.lastname: Bobb
authors.forename: F
authors.initials: F
authors.lastname: Yang
mesh_terms: D000397:Air Pollution; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002244:Carbon / Q000494:pharmacology; D060729:Coal Ash; D004586:Electrophoresis; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000032:analysis; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007781:Lactoferrin / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D052638:Particulate Matter; D017354:Point Mutation; D012326:RNA Splicing; D012806:Siderosis / Q000378:metabolism; D014168:Transferrin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D060729:Coal Ash; D016877:Oxidants; D052638:Particulate Matter; D014168:Transferrin; D002244:Carbon; D005293:Ferritins; D007501:Iron; D007781:Lactoferrin