Last year, research at Washington University revealed a connection between time of day and immune function in the lungs: a lung circadian rhythm. The same investigators are now studying how disruptions in that rhythm affect response to active infection. Their findings may steer development of new approaches to treating respiratory diseases.
Studying mice, the investigators discovered that lung immune function displayed a circadian rhythm; the number and types of immune cells trafficking through the lung varied regularly over time, as did the expression of genes that impact inflammation.
The discovery actually grew from research on the liver, as the researchers studied the protein breakdown that occurs there in sepsis, the body’s overwhelming immune response to infection, says lead investigator Jeffrey Haspel, MD, PhD. In mouse models, they found that the rate of protein breakdown—already known to rise in critically ill patients—not only varied greatly over time, but followed a circadian rhythm.
The genetic way lungs tell time
“Now that we knew circadian rhythms affected sepsis, we wondered about their effect in the lungs,” Haspel says. “It turns out circadian rhythms are intrinsic in the lungs. Lungs have a genetic way to tell time.”
In their pulmonary studies, they examined patterns of gene expression in the lungs of mice every four hours for two to three days. Some of the mice were healthy, and others were given a bacterial product to inflame the lungs. Not only were circadian rhythms apparent, but they were altered in the mice whose lungs were inflamed.
For example, in healthy mice, the immune B cells in the lungs had a circadian rhythm, but in mice with inflamed lungs, that rhythm appeared instead in other immune cells called granulocytes, which include neutrophils and macrophages. Further, these granulocyte rhythms influenced the lungs such that “danger signals”—small molecules that promote inflammation—displayed rhythmic patterns as well.
The research was published in the September 2014 Nature Communications.
Jet lagged lungs
The investigators are now studying the consequences of disrupting lung circadian rhythms when a respiratory infection is present. They are looking at mice with mutations in circadian clock genes as well as mice subjected to “jet lag” through altered lighting conditions. After exposing the mice to common respiratory viruses, they are examining the severity of illness that results.
Regarding human implications, Haspel says: “About 20 percent of long-haul jet travelers report symptoms of a common cold a week after they travel. Most people blame this on recirculated air on planes, but maybe jet lag itself affects the circadian clock and the clock disrupts the immune system.”
They also are studying the expression of circadian clock genes in children who have been hospitalized for viral infections such as respiratory syncytial virus (RSV).
“Kids who are hospitalized with respiratory infections have an increased risk of later developing asthma,” Haspel says. “We are interested in how differences in circadian rhythms can make these kids sicker or more likely to develop asthma—or, if they already have asthma, more likely to have an exacerbation.”
An important clinical implication is the possibility of developing drugs that more effectively treat respiratory diseases such as asthma.
“If we look at time-related aspects of the disease—almost all patients with asthma have worse symptoms at night, for example—it might yield more broadly applicable drugs down the line,” Haspel says.