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Molecule helps cells plug leaks following lung injury

September 15, 2006

Researchers at the University of Illinois at Chicago College of Medicine have identified a molecule that plays a critical role in the recovery of lung tissue following severe injury.

The study appeared in the Sept. 1 issue of the Journal of Clinical Investigation.

In acute lung injury - usually resulting from infection, inflammation or surgical trauma - cells that line the blood vessels in the lung lose their ability to form a barrier, allowing fluid to seep into the lung's air spaces and resulting in respiratory failure. Such damage is a significant cause of death in critically ill patients.

Very little is known about how the lung repairs this lining layer, called the endothelium, said You-Yang Zhao, research assistant professor of pharmacology.

"We thought it likely that the ability of cells to repair and restore the endothelium might depend on their ability to proliferate and fill in gaps in the endothelial monolayer barrier that allow leaking," said Zhao, who is lead author of the study.

Earlier studies had shown that FoxM1, a protein that controls the expression of genes, plays a critical role in cell proliferation. Working with the late Robert Costa, professor of biochemistry and molecular genetics at UIC, whose research focused on FoxM1, the researchers developed a mouse model that lacked the FoxM1 gene only in endothelial cells.

In the study, lung injury was induced in normal mice and in the gene-deleted mice. Blood vessels in the FoxM1-deficient mice continued to leak fluid, and the mice were significantly less likely to recover, resulting in a seven-times-greater mortality rate.

Although the immune response of each group was similar, there was less endothelial cell proliferation in the gene-deficient mice after the injury, suggesting that inability to fill the gaps in the barrier with new cell growth impaired the ability to recover.

Asrar Malik, professor and head of pharmacology at UIC, says the results suggest that lung injury activates a repair program, mediated by FoxM1, that encourages cell growth and restores the barrier integrity.

"This suggests future therapies for acute lung injury that target this molecule could promote endothelial regeneration and the patient's recovery," said Malik, who is senior author of the paper.

University of Illinois at Chicago