Iron In The Blood, Good; Iron In The Lung, Very Bad

But put iron or other air-borne particulates into our lungs and theycan cause health problems ranging from asthma and acute respiratorydistress syndrome to asbestosis and lung cancer.

In a recently-published paper a group of EPA-led lung researchersreported experiments demonstrating for the first time that "DMT1 isessential for the transport and detoxification of some metalsassociated with an air pollution particle that damages the pulmonaryepithelial surface."

The paper "Divalent metal transporter-1 decreases metal-related injuryin the lung" appears in the American Journal of Physiology-LungCellular and Molecular Physiology, published by the AmericanPhysiological Society. Research was performed by Andrew J. Ghio, LisaA. Dailey, Jacqueline D. Stonehuerner and Michael C. Madden from theU.S. Environmental Protection Agency; Claude A. Piantadosi of DukeUniversity; Xinchao Wang of University of North Carolina; Funmei Yangof University of Texas; and Kevin G. Dolan, Michael D. Garrick andLaura M. Garrick of SUNY-Buffalo.

Lead researcher Andrew Ghio said this breakthrough discovery ofDMT1 lung protection could prompt studies of its roles in other organswhere it's found. "For instance, DMT1 is in the liver, kidneys andbrain, where it's not needed for nutritional purposes," Ghio said, "andsince iron is implicated in everything from infections to cancers, it'snot unreasonable to believe DMT1 could serve as a therapeutic target inthose, as well as even Alzheimer's."

Florida 'oil fly ash' tests in normal and DMT1-deficient rats, and in vitro

Using an "oil fly ash" high in iron and vanadium collected froma Florida power plant burning low sulfur oil as the insult, theresearchers tested exposure to normal rats as well as "Belgrade" rats,which are functionally deficient in DMT1 because of a mutation. Theyalso performed parallel tests in vitro, as well as testing how"pre-conditioning" with various foreign metallic insults might affectgene expression and resulting lung damage.

One key to how DMT1 works is by generating two alternativelyspliced messenger RNAs that differ by the presence (+) or absence (-)of an Iron-Response Element (thus -IRE or +IRE). In contrast to thegastrointestinal tract where the +IRE form dominates, there is more-IRE DMT1 in the lung. The paper noted that in the lung, "there is anIRE-independent iron-regulatory pathway for control of DMT1 expressionof the -IRE isoform of DMT1, whereas the +IRE isoform shows littleresponse to the metal."

Results show DMT1 doesn't pose risk for cellular damage, but may prevent it

The authors said that before their results, it could have beenargued that "the chain of events described here (iron exposureincreasing -IRE DMT1 expression leading to metal uptake withsequestration of iron) ... is just a set of associations." However, theBelgrade data "rule out these alternatives and support the argumentthat this chain of events is a set of causal relationships because(these rats) have defective DMT1," which diminishes transport activity."This transport deficiency in the Belgrade rat renders this animalineffective at controlling the oxidative stress presented by the (ash)particle, so that greater tissue injury results.

"While there is room for other explanatory hypotheses thatconnect the injury to the defective DMT1, one can no longer maintainthat higher DMT1 activity places cells at higher risk of damage," thepaper noted.

Protective mechanism shuts out too-toxic elements, keeps iron away from microbes

An interesting finding was that "exposure of respiratoryepithelial cells to vanadium decreased both mRNA and expression of-IRE. Among multiple metals we have tested (though data wasn't reportedin the paper), iron alone has increased -IRE DMT1 mRA while vanadiumand arsenic have decreased it." Ghio said later that they believe thisis because the lung is designed to handle the iron particles, but thatvanadium is so toxic that the cells realize they can't cope and so theyshut down the transport mechanism.

The paper noted that since the presence of iron increases "DMT1messenger-RNA and function, we suspect that the lung may have evolved aspecific response to iron in order to protect the epithelial surfacefrom oxidative stress.... Management of iron in particles is alsocritical to minimize the metal ions' availability to microbial invadersthat may arrive with the same particles," it added.

The paper also demonstrated "that control of DMT1 experession inrespiratory epithelial cells differs from that in the intestine because-IRE mRNA and protein are upregulated by iron, resulting in cellulariron uptake, and limiting the reactive oxygen species generated by ironand other redox-active metals."

Next steps

Ghio said the mechanisms uncovered in their experiments so farindicate that "if we follow the iron, we may be able to change thetypes of toxic reactions to all kinds of particulates and fibers andthe metals they carry." In addition, since iron is involved in so manyhealthy and diseased states throughout the body further study will beneeded to define its role. He pointed out that research already isunderway to see what functions DMT1 might be playing in the otherorgans where it is found, including the liver, kidney and brain.

Source and funding

The paper "Divalent metal transporter-1 decreases metal-relatedinjury in the lung" appears in the American Journal of Physiology-LungCellular and Molecular Physiology, published by the AmericanPhysiological Society. Research was performed by Andrew J. Ghio, LisaA. Dailey, Jacqueline D. Stonehuerner and Michael C. Madden from theU.S. Environmental Protection Agency's National Health andEnvironmental Effects Research Laboratory, Research Triangle Park,North Carolina (NC); Claude A. Piantadosi of Duke University MedicalCenter's Department of Medicine, Durham, NC; Xinchao Wang of Universityof North Carolina's Center for Environmental Medicine and Lung Biology,Chapel Hill, NC; Funmei Yang from the Dept. of Cellular and StructuralBiology, University of Texas Health Science Center, San Antonio; andKevin G. Dolan, Michael D. Garrick and Laura M. Garrick of the Dept. ofBiochemistry, State University of New York, Buffalo.

Research was partially funded by NIH/ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).