title: Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury.
abstract: Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ~4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Lee
authors.forename: Joseph N
authors.initials: JN
authors.lastname: McLaughlin
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Frederick
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Kalidasan
authors.initials: K
authors.lastname: Thambiayya
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Wasserloos
authors.forename: Iris
authors.initials: I
authors.lastname: Kaminski
authors.forename: Linda L
authors.initials: LL
authors.lastname: Pearce
authors.forename: Jim
authors.initials: J
authors.lastname: Peterson
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Latoche
authors.forename: Octavia M
authors.initials: OM
authors.lastname: Peck Palmer
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Fattman
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D005260:Female; D018496:Hyperoxia; D007249:Inflammation / Q000276:immunology; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000032:analysis; D020545:Respiratory Mucosa / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D008668:Metallothionein; D013482:Superoxide Dismutase; D015032:Zinc