Molecular Details of Water Transport in the Lung Identified

January 22, 2002

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HOPKINS SCIENTISTS IDENTIFY MOLECULAR DETAILS OF WATER TRANSPORT IN THE LUNG

We may sputter and gasp when our drink goes down the wrong pipe, but fluid is vital to a healthy lung. The crucial movement of water across cell membranes in the lung was long thought to be a passive process, but a team of researchers from Hopkins and the University of Aarhus in Denmark have demonstrated that a specific protein plays a major role. The discovery may lead to new treatments for some forms of asthma, pneumonia and pulmonary edema or swelling.

"This is the first study to show that the protein, called aquaporin-1, plays a role in lung function," says Landon King, M.D., assistant professor of pulmonary medicine and lead author of the study. "The aquaporin-1 protein is a water channel that regulates water movement into and out of cells and thus may provide a distinct target for the development of therapies for a variety of lung diseases."

The regulation of water movement is a fundamental requirement at all levels of life, yet the pathway that water follows to cross a cell membrane was unknown until recently, says King. In the early 1990s, Peter Agre, M.D., a Hopkins professor of biochemistry, discovered a protein that formed a channel or pore through which water could travel into and out of the cell. Since then, scientists have identified 10 aquaporin proteins, and similar versions of the molecule exist in all forms of life, including bacteria, yeast and plants.

In the current study, reported in the Jan. 22 issue of the Proceedings of the National Academy of Sciences, King and Robert Brown, M.D., associate professor of anesthesiology and critical care medicine at Hopkins, compared lung function in five normal people with lung function in two very rare individuals without the protein but with otherwise normal lungs. The researchers used high-resolution CT scans to monitor blood vessel size and thickness of adjacent airway walls where water regulation is extremely important. To promote the flux of water across blood vessel walls, intravenous injections of saline were given under careful supervision.

"People who have aquaporin-1 clearly responded differently than the protein-deficient individuals," says King. The size of the blood vessels increased equally in both groups, suggesting the increase in fluid volume from the infusions was the same. However, airway wall thickness increased by 40 percent to 50 percent in the normal individuals, while there was absolutely no change in the protein-deficient individuals.

In normal lungs, a fluid challenge like this causes leakage of water through aquaporin-1 and swelling in the space around the airways, a condition known as peribronchial edema or cuffing, but without the protein there was no leakage of fluid and no change in the size of the airway walls.

"This suggests that water permeability is independently regulated," says King. The passive movement of water and solutes across cell membranes is still very important to lung function, and in people who lack the protein it may be vitally important, but these experiments reveal that aquaporin-1 plays a role in normal lung physiology.

"Aquaporin-1 may be a good target for developing therapies where water regulation is crucial to the functioning of the organ, including the lungs and kidneys," says King.

King's team demonstrated the role of aquaporin-1 in kidney function last summer. Future research on aquaporin-1 will investigate the expression, stability and movement of the protein, as well as its behavior in different animals and humans.

In addition to King, Agre and Brown, Soren Neilsen from the University of Aarhus in Denmark is a co-author of the study. The study was funded by the National Institutes of Health, the Cystic Fibrosis Foundation, the European Commission and the Karen Elise Jensen Foundation.

Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 2, 1059-1063, January 22, 2002

Related Web sites:

The Johns Hopkins Division of Pulmonary and Critical Care Medicine: http://www.hopkins-lungs.org/

Media Contact: Trent Stockton 410-955-8665Email: [email protected]

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