Divalent metal transporter-1 decreases metal-related injury in the lung

Oct 4 2005

Multi-vitamin products, nutritional supplements and parents tout the need for such mineral elements as calcium, zinc, phosphorus, iron and others.

Iron, for example, is a nutritional prerequisite to power life itself. When blood doesn't get enough iron from the gut, we become anemic. One of the body's coping mechanisms is to produce more of a protein called divalent metal transporter 1 (DMT1) in the gastrointestinal lining cells to bring into the body as much iron as possible. Until recently DMT1 was exclusively studied for its nutritional role in transporting iron.

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

In a recently-published paper a group of EPA-led lung researchers reported experiments demonstrating for the first time that "DMT1 is essential for the transport and detoxification of some metals associated with an air pollution particle that damages the pulmonary epithelial surface."

The paper "Divalent metal transporter-1 decreases metal-related injury in the lung" appears in the American Journal of Physiology-Lung Cellular and Molecular Physiology, published by the American Physiological Society. Research was performed by Andrew J. Ghio, Lisa A. Dailey, Jacqueline D. Stonehuerner and Michael C. Madden from the U.S. Environmental Protection Agency; Claude A. Piantadosi of Duke University; Xinchao Wang of University of North Carolina; Funmei Yang of University of Texas; and Kevin G. Dolan, Michael D. Garrick and Laura M. Garrick of SUNY-Buffalo.

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

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

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

The authors said that before their results, it could have been argued that "the chain of events described here (iron exposure increasing –IRE DMT1 expression leading to metal uptake with sequestration of iron)…is just a set of associations." However, the Belgrade data "rule out these alternatives and support the argument that 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 animal ineffective at controlling the oxidative stress presented by the (ash) particle, so that greater tissue injury results.

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

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

The paper noted that since the presence of iron increases "DMT1 messenger-RNA and function, we suspect that the lung may have evolved a specific response to iron in order to protect the epithelial surface from oxidative stress….Management of iron in particles is also critical to minimize the metal ions' availability to microbial invaders that may arrive with the same particles," it added.

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

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