title: Sequestration of mitochondrial iron by silica particle initiates a biological effect.
abstract: Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica reduced intracellular iron, which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial (57)Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Preincubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation, but pretreatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-κB and NF-E2-related factor 2), proinflammatory cytokines (interleukin-8 and -6), and apoptotic proteins. All of these changes in indexes of biological effect were either diminished or inhibited by cell pretreatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica were decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.
authors.affiliation: Human Studies Facility, 104 Mason Farm Road, Chapel Hill, NC. ghio.andy@epa.gov.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tong
authors.forename: Joleen M
authors.initials: JM
authors.lastname: Soukup
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Dailey
authors.forename: Wan-Yun
authors.initials: WY
authors.lastname: Cheng
authors.forename: James M
authors.initials: JM
authors.lastname: Samet
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kesic
authors.forename: Philip A
authors.initials: PA
authors.lastname: Bromberg
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Turi
authors.forename: Daya
authors.initials: D
authors.lastname: Upadhyay
authors.forename: G R
authors.initials: GR
authors.lastname: Scott Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005293:Ferritins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D052638:Particulate Matter / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012822:Silicon Dioxide / Q000494:pharmacology*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D005293:Ferritins; D015850:Interleukin-6; D016209:Interleukin-8; D007501:Iron; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D016877:Oxidants; D052638:Particulate Matter; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012822:Silicon Dioxide; D000099236:Solute Carrier Family 11, Member 2
keywords: inflammation; oxidants; particulate matter; quartz