Asthma study turns up new information on viral infections

Researchers know that viral infections can exacerbate asthma and, in turn, make people with the condition more sensitive to environmental exposures such as endotoxin. But how viral infections contribute to this sensitivity in airway cells has not been clear. A recent study led by investigators from the University of Iowa Roy J. and Lucille A. Carver College of Medicine and the Veterans Affairs Medical Center (VAMC) in Iowa City shows, for the first time, that viral infections may increase environmental sensitivity in lung epithelial (surface) cells by changing expression of receptors on those cells.

Using cell models, the team specifically showed that respiratory syncytial virus (RSV) infection increases the number of a type of receptor called Toll-4 on the airway cells. This Toll-4 receptor can provide a foothold for inhaled endotoxin, a naturally occurring environmental contaminant that comes from bacteria and is found in household dust, grain dust and objects such as pillows. The presence of receptors for endotoxin would lead to interaction between the epithelial cell and the endotoxin and potentially cause inflammation. The study appeared in the December 26, 2003, issue of the Journal of Biological Chemistry.

"The big picture here is that viral infections may upregulate, or increase, one or more receptors on the airway cells and make them more sensitive to environmental exposures. This could explain the viral-induced asthma exacerbations seen in people with asthma," said Martha Monick, senior research assistant in the Division of Pulmonary, Critical Care and Occupational Medicine in the UI Department of Internal Medicine and the study's co-lead author.

Monick said the inspiration for the study came when the team put endotoxin on normal airway epithelial cells and noticed there was no inflammatory response.

"This puzzled us, so we started thinking about receptors on lung cells," Monick said. "When we looked in normal lung cells for the receptors for endotoxin, we found there were very low levels and they were inside the cell, not on the surface."

With that observation, the investigators wanted to see what happened to endotoxin receptors when lung cell models were infected by a virus. The team used RSV, which normally does not cause serious illness in healthy people but has epidemiological links to asthma and asthma exacerbations. They found that this virus increased both the amount and the surface expression of the receptors for endotoxin on cells lining the airway. Next, they exposed RSV-infected lung cells to endotoxin and saw the increased inflammatory response.

"The increased expression of the Toll-4 receptor after the viral infection markedly increased the sensitivity of the epithelial cells to endotoxin exposure," said Gary Hunninghake, M.D., a study author and the Sterba Professor of Internal Medicine with the UI Carver College of Medicine and a researcher and staff physician with the Iowa City VAMC.

The increased endotoxin response results in proteins that cause inflammation, constricting the airways of people with asthma. It is likely that viruses also increase the response of the airways to other environmental exposures. This increased non-specific response of asthmatic airways to environmental exposures is a typical feature of asthma, Hunninghake said.

"The next phase of these studies is to determine if viruses cause the same effect in individuals with asthma," said Hunninghake, who directs the UI Division of Pulmonary, Critical Care and Occupational Medicine and also directs the Graduate Program in Translational Biomedicine.

The team will study if the change they saw in receptor expression after RSV infection will occur in animal models of asthma and in cells taken from nasal washes of patients with asthma.

In addition to Monick and Hunninghake, the team included co-lead author Timur Yarovinsky, Ph.D., UI assistant research scientist in internal medicine. Gunnar Gudmundsson, M.D., Ph.D., a former UI fellow in internal medicine now at the National University Hospital in Reykjavik, Iceland, also contributed to the study.