Source: American Physiological Society
http://www.sciencedaily.com/releases/2005/10/051004084839.htm
Source: American Physiological Society
Date: 2005-10-04
Iron In The Blood, Good; Iron In The Lung, Very Bad
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 [censored] 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."
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 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."
Results show DMT1 doesn't pose risk for cellular damage, but may
prevent it
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.
Protective mechanism shuts out too-toxic elements, keeps iron away from
microbes
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."
Next steps
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.
###
Source and funding
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's National Health and
Environmental Effects Research Laboratory, Research Triangle Park,
North Carolina (NC); Claude A. Piantadosi of Duke University Medical
Center's Department of Medicine, Durham, NC; Xinchao [censored] of University
of North Carolina's Center for Environmental Medicine and Lung Biology,
Chapel Hill, NC; Funmei Yang from the Dept. of Cellular and Structural
Biology, University of Texas Health Science Center, San Antonio; and
Kevin G. Dolan, Michael D. Garrick and Laura M. Garrick of the Dept. of
Biochemistry, State University of New York, Buffalo.
Research was partially funded by NIH/ National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK).
Editor's Note: The original news release can be found here.
--------------------------------------------------------------------------------
This story has been adapted from a news release issued by American
Physiological Society.
Who loves ya.
Tom
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