Lung injury after ozone exposure is iron dependent.
We tested the hypothesis that oxidative stress and biological effect after ozone (O3) exposure are dependent on changes in iron homeostasis. After O3 exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after O3 exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following O3 inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to O3. Iron homeostasis was disrupted to a greater extent and the extent of injury was greater in Belgrade rats than in control rats. Nonheme iron and ferritin concentrations were higher in human bronchial epithelial (HBE) cells exposed to O3 than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following O3 exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and O3. With exposure to O3, elevated DMT1 expression diminished oxidative stress (i.e., aldehyde generation) and IL-8 release. We conclude that iron participates critically in the oxidative stress and biological effects after O3 exposure.
Ghio
Andrew J
AJ
Human Studies Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, 104 Mason Farm Rd., Chapel Hill, NC 27599-7315, USA. ghio.andy@epa.gov
Turi
Jennifer L
JL
Madden
Michael C
MC
Dailey
Lisa A
LA
Richards
Judy D
JD
Stonehuerner
Jacqueline G
JG
Morgan
Daniel L
DL
Singleton
Steven
S
Garrick
Laura M
LM
Garrick
Michael D
MD
D000293:Adolescent; D000328:Adult; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D027682:Cation Transport Proteins / Q000172:deficiency; D002460:Cell Line; D004195:Disease Models, Animal; D005293:Ferritins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007781:Lactoferrin / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D008297:Male; D018384:Oxidative Stress; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D005293:Ferritins; D007501:Iron; D007781:Lactoferrin; D010126:Ozone; D011990:Receptors, Transferrin; D014168:Transferrin; D000099236:Solute Carrier Family 11, Member 2