Many children who get a severe skin rash develop asthma months or years later. Doctors call the progression from eczema, or atopic dermatitis, to breathing problems “the atopic march.”
Now School of Medicine scientists have uncovered what might be the key to atopic march. They’ve shown that a substance secreted by damaged skin circulates through the body and triggers asthmatic symptoms in allergen-exposed laboratory mice.
The findings, published May 19 in Public Library of Science Biology, suggest that early treatment of skin rash and inhibition of the trigger substance might block asthma development in young patients with eczema.
Fifty percent to 70 percent of children with severe atopic dermatitis go on to develop asthma, studies show. By comparison, about 9 percent of children and 7 percent of adults in the general population have asthma. Seventeen percent of U.S. children suffer from atopic dermatitis, although not all cases are considered severe.
“Over the years, the clinical community has struggled to explain atopic march,” said study author Raphael Kopan, Ph.D., professor of developmental biology and of dermatology. “So when we found that the skin of mice with an eczema-like condition produced a substance previously implicated in asthma, we decided to investigate further. We found that the mice also suffered from asthma-like responses to inhaled allergens, implicating the substance, called TSLP (thymic stromal lymphopoietin), as the link between eczema and asthma.”
Doctors and scientists had developed theories to explain why a skin rash is sometimes associated with asthma. Kopan’s findings suggest the problem starts with damaged or defective skin. The researchers found that cells in damaged skin can secrete TSLP, a compound capable of eliciting a powerful immune response. And because the skin is so effective in secreting TSLP into the blood, the substance travels throughout the body. When it reaches the lungs, it triggers the hypersensitivity characteristic of asthma.
Led by Shadmehr (Shawn) Demehri, a doctoral student in the Division of Biology and Biomedical Sciences, the researchers studied mice that had been engineered with a genetic defect in patches of their skin. In the affected areas, the typically ordered layers of skin cells were disrupted, creating a condition similar to eczema. These patches were thickened and inflamed. The defective skin secreted TSLP, activating an immune response that fights invaders.
Assuming that other barrier organs such as the lung would understand this alarm, the researchers tested what happened when the mice with skin defects inhaled an allergen. They found that their lungs reacted strongly — their breathing became labored and their lung tissue took on the traits that mark asthma in humans: mucous secretion, airway muscle contraction, invasion by white blood cells and conversion of lung cells from one type to another. Additional experiments showed that mice that had normal skin but were engineered to overproduce TSLP also developed the asthma-like symptoms.
“We are excited because we’ve narrowed down the problem of atopic march to one molecule,” Kopan said.
“We’ve shown that skin can act as a signaling organ and drive allergic inflammation in the lung by releasing TSLP,” he said. “Now it will be important to address how to prevent defective skin from producing TSLP. If that can be done, the link between eczema and asthma could be broken.”
TSLP is also produced in the lungs of asthma patients, and Kopan said that research in the skin could lead to ways to interfere with TSLP made in the lungs and thereby ease asthma development even in cases that aren’t linked to eczema.