|
Physicians well know that too little oxygen (hypoxia) causes headaches, nausea, and eventually death. But too much oxygen (hyperoxia) kills, too. In a new study in the open-access journal PLoS Biology, a team led by Michail Sitkovsky show that oxygenation weakens a tissue-protecting mechanism triggered by hypoxia.
Hypoxia triggers a signaling pathway mediated by an adenosine receptor (called A2AR) that arrests inflammation and tissue damage; the researchers show that this same hypoxia-driven pathway protects the lungs from the toxic effects of overactive immune cells called neutrophils. Working with gene-altered mice, the team of immunologists, pathologists, and biochemists found evidence that clinical oxygenation treatments could aggravate lung injury by inhibiting this protective pathway. But this protective pathway could potentially be restored, they argue, by artificially activating the inhibited pathway with therapeutic activators.
Hypoxia protects against lung damage, the authors found, by working through the A2AR signaling pathway to control inflammation. Above-normal oxygen levels interrupt this anti-inflammatory pathway, paving the way for further lung injury. Administering a molecule that jump-starts A2AR signaling artificially also significantly reduced the pathological side effects of oxygenation.
These results may help explain why some patients with acute respiratory distress syndrome (ARDS) and lung inflammation die following oxygenation therapy, which is designed to facilitate oxygen delivery to oxygen-deprived tissues. And by identifying the mechanism that is disrupted by oxygenation - A2AR signaling - this study suggests that therapies aimed at activating the anti-inflammatory A2AR pathway may allow patients to receive the benefits of oxygenation therapy without succumbing to its toxic effects.
Citation: Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, et al. (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3(6): e174.
CONTACT:
Michail Sitkovsky
National Institute of Allergy and Infectious Diseases
10 Center Drive
Bldg. 10, Room 11N311
Bethesda, MD USA 20892
+1-301-806-6404
+1-301-496-5495 (fax)
m.sitkovsky@neu.edu
PLEASE MENTION PLoS Biology (www.plosbiology.org) AS THE SOURCE FOR THESE ARTICLES. THANK YOU.
All works published in PLoS Biology are open access. Everything is immediately available without cost to anyone, anywhere--to read, download, redistribute, include in databases, and otherwise use--subject only to the condition that the original authorship is properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.
Journal
PLoS Biology