National Institute of Allergy and Infectious Diseases (NIAID)

EXCESS OXYGEN WORSENS LUNG INFLAMMATION IN MICE

NATIONAL INSTITUTES OF HEALTH

NIH News

National Institute of Allergy and Infectious Diseases (NIAID)
http://www.niaid.nih.gov/default.htm

EMBARGOED FOR RELEASE
Monday, May 2, 2005

CONTACT:
Anne A. Oplinger
301-402-1663
aoplinger@niaid.nih.gov

EXCESS OXYGEN WORSENS LUNG INFLAMMATION IN MICE

Research performed at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has revealed that oxygen therapy aimed at helping mice with acute lung inflammation breathe paradoxically worsened their illness. The researchers say excess oxygen appears to thwart a natural process that limits lung tissue damage.They overcame this deleterious side effect, however, by adding an inhaled anti-inflammatory drug to the oxygen therapy.

"This research illustrates, in an animal model, a delicate balance between supplemental oxygen therapy and an innate tissue-preserving process
that appears to operate best in low-oxygen conditions," says NIAID Director
Anthony S. Fauci., M.D.

Michail Sitkovsky, Ph.D., senior author of the paper published this week in
the journal "PLoS Biology", believes the findings could have clinical implications. Supplemental oxygen is a life-saving therapy for patients with
breathing problems, but it can harm the lungs if it is used for long periods. While the problem of oxygen-induced lung damage is well known, the biochemical processes leading to this damage have not been fully explained.
Dr. Sitkovsky's research reveals a possible mechanism behind this
oxygen-induced damage and also provides evidence of a simple way to prevent it.

The current study extends research published in 2001 by Dr. Sitkovsky
and colleagues into the role played by the molecule adenosine in regulating
inflammation. Inflammatory chemicals produced by the immune system in
response to infection or injury must eventually be switched off so that
excessive tissue damage can be avoided. Dr. Sitkovsky and his colleagues
have shown that inflammation leads to a drop in oxygen levels in the
inflamed tissues. This, in turn, triggers the release of adenosine from
surrounding cells. When adenosine binds to cell receptors in the inflamed
region, it serves as a tissue-protecting stop signal, slowing the flood of
damaging inflammatory molecules, the scientists found.

From these findings, they reasoned that oxygen therapy given to patients
with acute lung inflammation might "short-circuit" this protective pathway
by preventing oxygen levels from dropping enough to trigger the inflammation
stop signal.

To explore this possibility in an animal model, Dr. Sitkovsky and his
colleagues induced lung inflammation in three groups of mice. The first
group of 15 mice did not receive any supplemental oxygen. While they
sustained moderate lung damage, only two died. Another group of 15 mice
with acute lung inflammation were treated with either 100 percent or 60
percent oxygen for 48 hours. These mice suffered very extensive lung damage, and 11 of 15 died. Finally, the scientists treated another 15 mice with acute lung inflammation with a combination of 100 percent oxygen and an
adenosine-like drug to compensate for the oxygen-induced loss of natural adenosine. Only two mice in this group died, and exacerbation of lung inflammation by oxygen was prevented.

The investigators conclude that in this small animal model highly pure oxygen therapy without the addition of an adenosine substitute worsens pre-existing lung inflammation. "We suggest that these adenosine substitutes be evaluated for their possible usefulness in settings of acute lung inflammation due to infection or other causes, such as asthma or surgical trauma," says Dr. Sitkovsky.

Dr. Sitkovsky is now continuing his research at the newly established
New England Inflammation and Tissue Protection Institute, a consortium at
Northeastern University in Boston.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses,
including autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.

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References: A Ohta and M Sitkovsky. Role of adenosine receptors in down-regulation of inflammation and protection from tissue damage.
"Nature"
414:916-20 (2001).

M Thiel et al. Oxygenation inhibits the physiological tissue-protecting
mechanism and thereby exacerbates acute inflammatory lung injury. "PLoS
Biology" 2(6): e174 (2005). DOI: 10.1371/journal.pbio.0030174.

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This NIH News Release is available online at:
http://www.nih.gov/news/pr/may2005/niaid-02.htm.