Key to acute lung injury lies in Ang2 protein

Acute lung injury caused by cell death, high and potentially toxic concentrations of oxygen (hyperoxia), and the resulting excess fluid in the lungs (pulmonary edema), may be controlled by modulating levels of the angiopoietin2 (Ang2) protein, researchers at Yale School of Medicine report in the November 5 online issue of Nature Medicine.

The study, which was completed in the laboratory of senior author Jack Elias, M.D., the Waldemar Von Zedtwitz Professor and chair of internal medicine at Yale, looked at the response to hyperoxic acute lung injury (HALI), first in mice and then in human adults and babies. The team found that mice in which the Ang2 gene was genetically eliminated or silenced lived longer and had evidence of decreased lung injury compared to mice in which the gene and protein were intact.

Levels of the Ang2 protein were then measured in the blood and lung fluid of adult patients and babies with acute lung damage and pulmonary edema. The team found that levels of Ang2, which is known to increase leaks in blood vessels and causes the death of endothelial cells that line the blood vessels, were higher in adult patients with acute lung injury and in babies born with respiratory distress syndrome who either went on to develop bronchopulmonary dysplasia or died.

"Mice without Ang2 seemed to be protected against hyperoxia," said first author Vineet Bhandari, M.D., assistant professor of pediatrics at Yale School of Medicine. "This protein seems to be a mediator of cell death in the settings of high oxygen concentrations in the lung causing acute lung injury and pulmonary edema."

Bhandari said the study is an example of true bench-to-bedside translational research. "All the work was initially done on mice in which we found that the Ang2 protein was involved in HALI," said Bhandari. "We also defined how the protein creates lung injury and then we showed its clinical relevance by documenting its presence in human patients with acute lung injury."

In addition to acute lung injury and pulmonary edema, Bhandari said, an increase in Ang2 and cell death can be seen in other disorders such as heart attacks, stroke, eye disease in diabetics and brain tumors.

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Other Yale authors on the study included Rayman Choo-Wing, Chun G. Lee, Zhou Zhu, Jonathan Nedrelow, Geoffrey Chupp, Xuchen Zhang, Michael Matthay, Lorraine Ware, Robert Homer and Patty Lee. The team collaborated with Anke Geick and Antonin R. de Fougerolles of Alnylam Pharmaceuticals, a biotechnology company focused on RNA interference (RNAi) therapeutics, which was used to silence the Ang2 gene.

Citation: Nature Medicine, (Published online November 5, 2006)


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