Discovering an Environmental Cause of Asthma
With the incidence of asthma continuing to rise among children in the inner city, research underway at the Cincinnati Children's Division of Critical Care Medicine may help to explain why, and eventually, offer alternative therapeutic options.
A new study led by Kristen Page, PhD, focuses on the direct effect cockroach extract has on the airway epithelium. Because the airway epithelium is the first line of contact with airborne allergens, the research examines how proteases in cockroach extract modulate or enhance the inflammatory response in human bronchial epithelial cell lines.
"We found that this protease activity is important in modulating the regulation of IL-8, which commonly appears in the sputum of children with asthma," Dr. Page says.
How does this happen?
By breathing in dust, an individual inhales cockroach proteases. Once inside the body, this enzyme clips off a piece of the protease-activated receptor.This cleavage activates extracellular- signal-regulated kinase (ERK), a common signaling intermediary that turns on growth and differentiation activities and cytokine regulation. ERK turns on the transcriptional factors that go to the nucleus, bind to the gene and produce IL-8.This protein is then released into the sputum, causing neutrophils and eosinophils to rush to the area – and creating one of the hallmarks of asthma.
"This paper demonstrates that proteases can cause the epithelial cells to react directly. In other words, these proteases in cockroach extract may cause asthma to get worse," Dr. Page explains.
What Is This Protease?
How proteases modulate airway inflammation is the focus of Dr. Page's work. She is studying two main questions. In the airway epithelium, what factors are being moderated by this cockroach protease? And secondly, what is this protease? It is in the process of being purified for further study.
The biochemist theorizes that the protease is probably contained in salivary or fecal excretions that dry up, causing proteins to be released into dust and eventually inhaled by humans. "There are four known cockroach allergens that mediate the IgE response, but none of them has protease activity," she says."But we haven't pulled out everything that can modulate asthma.The dust mite has been studied more."
Dr. Page has collaborated with Bruce Lanphear,MD, MPH, in the Division of General and Community Pediatrics at Cincinnati Children's, to study the levels of cockroach allergens in carpet dust gathered from the homes of children with clinically diagnosed asthma."We found a correlation between the amount of cockroach in a sample and the level of protease activity.We also added dust to epithelial cells and found that when cockroach levels were high, IL-8 was released.The effect was entirely due to active proteases in the dust," she says.
New Treatments Possible
To study further the environmental aspects of cockroach-induced asthma, Dr. Page is working on obtaining a grant from the National Institutes of Health."This research is very relevant to our other studies.We don't believe that the proteases die with the cockroach, so we want to know more about how long they remain active in a home," she says.
Dr. Page notes that her laboratory is the only one currently studying this cockroach protease and its role in the airway.The next step is to move the research into mouse models. Looking to the future, her lab's findings may have therapeutic implications for children with asthma.
"We may find that there's something other than – or in addition to – corticosteroids that we can give to kids with asthma. Depending on how proteases actually regulate inflammation,we may be able to use protease inhibitors.We don't really know yet the importance of proteases."
This study was published in the Journal of Allergy & Clinical Immunology (112[6]:1112-1118, 2003 December) and was supported by grants from the American Lung Association and a Cincinnati Children's Research Foundation Trustee Grant.
