Winter 2006-07
NIAID Discovery News
A Potential New Target for Treating Asthma
Recent research results may have a marked impact on how asthma is treated in the future. In a mouse model of asthma, which closely resembles certain aspects of human asthma, NIAID grantees investigated the function of a specific protein, NF-ĸB, in the epithelial cells lining the airways of the lungs. Their findings demonstrate for the first time a critical role for this protein in the development of chronic asthma. Blocking the protein’s action reduced the level of eosinophils, a type of white blood cell involved in asthmatic airway inflammation, and inhibited remodeling of the airways. This discovery may lead to the development of a new class of therapeutics for treating asthma and other diseases of the lungs.
Characteristics of Asthma
Asthma, a respiratory disease of the lungs, affects more than 20 million Americans, including 9 million children, making it the most common serious chronic disease of childhood. It is characterized by episodes of inflammation and narrowing of the lower airways in response to asthma “triggers.” These triggers include infectious agents, stress, pollutants such as cigarette smoke, and common allergens such as cat dander, dust mites, and pollen.
When a person with allergic asthma is exposed to an allergen for the first time, the immune system responds by making IgE antibodies to the antigen. These antibodies then bind to the surface of mast cells. The person is now sensitized to the allergen, and upon re-exposure, the allergen binds to the antibody and the mast cells release chemical mediators that cause an asthma attack. During an asthma attack, the airways narrow almost immediately due to contractions of the surrounding smooth muscle; excess mucus is produced; and eosinophils and other inflammatory cells begin to accumulate, giving rise to the classic asthma symptoms of wheezing, coughing, chest tightness, and difficulty breathing. During a severe asthma attack, the airways may constrict so tightly that in rare cases, the individual dies.
The changes that occur during acute inflammation of the lower airways usually resolve as repair processes restore normal structure and function. However, a person with asthma who is repeatedly exposed to an allergen and goes through many cycles of inflammation and repair may develop permanent changes in the airways, called airway remodeling. These changes include 1) the development of excess fibrous connective tissue around the airways; 2) increases in the both the number and size of smooth muscle cells, resulting in more airway constriction when the muscles contract; and 3) increased numbers of mucus-secreting cells and increased mucus secretion.
Treating Asthma
Treatment for asthma, both acute and chronic, involves two main types of drugs that control asthma symptoms. Quick-relief medicines taken at the first signs of an asthma attack, such as inhaled bronchodilators, relax the smooth muscles surrounding the airways; for effective long-term control, individuals use corticosteroids, which reduce airway inflammation.
“About 10 percent of all asthmatic patients do not respond to these standard medications, and we need new treatments to help this subset of patients in particular,” says Michael Karin, Ph.D. of the University of California, San Diego (UCSD), one of the authors of the study. Moreover, he adds, current treatments only control asthma symptoms, they don’t cure them.
Dr. Karin’s research has focused on understanding the mechanism of airway remodeling with the goal of identifying potential therapeutic targets. In December 2005, he and his colleague, David H. Broide, M.B., Ch.B., at the UCSD, and their team of researchers published a paper describing the critical role played by the protein NF-ĸB in the development of airway remodeling. Their results suggest that blocking the activity of this protein, perhaps by using an inhaled inhibitor of the protein, may be an effective strategy for treating asthma and other lung diseases.
Although little is known about the complex mechanisms underlying airway remodeling, the research team hypothesized that bronchial epithelial cells and NF-ĸB are key players in the process. In asthma, the bronchial epithelium is structurally abnormal, and these cells have increased levels of gene expression and release chemicals involved in inflammation, called cytokines, and growth factors, including TGF-β1. In addition, NF-ĸB is a known master switch that controls the expression of many genes important for inflammation.
Investigating the Role of NF-ĸB in Airway Remodeling
To investigate whether NF-ĸB within epithelial cells of the airways is involved in allergen-induced airway remodeling, Drs. Broide and Karin and their colleagues used a mouse model of asthma they had developed previously. When these mice are repeatedly exposed to the allergen ovalbumin, a protein from eggs, they respond by becoming sensitized to ovalbumin and then develop chronic asthma. The airway remodeling that is observed appears to be similar to human airway remodeling.
The researchers genetically manipulated a subset of these mice to selectively knock out, or delete, the gene that encodes a protein called IKKβ in the epithelial cells of the airways. To function, NF-ĸB must be activated by an enzyme co mplex that includes IKKβ; by eliminating IKKβ, the researchers effectively prevented NF-ĸB activation. In epithelial cells lacking this gene, the levels of activated NF-ĸB were very low.
The researchers then compared what happened when the IKKβ-deficient mice and “normal” mice (those with the gene for IKKβ) are sensitized to ovalbumin and then are repeatedly exposed to ovalbumin. The researchers demonstrated that the mice deficient in activated NF-ĸB had lower levels of eosinophils in the lungs, significantly reduced buildup of fibrous tissue that surrounds the airways, and less mucus production.
“Eliminating the action of NF-ĸB dramatically reduced most of the airway remodeling that one sees, including buildup of fibrous tissue and mucus expression,” says Dr. Karin.
Adds Dr. Broide, “If you could make an inhaled therapy that inhibits NF-ĸB in the cells lining the bronchial tubes, you could potentially reduce both the scarring to the bronchioles and mucus production.”
It would not be beneficial, however, to block NF-ĸB throughout the entire body, he notes. Doing so would likely suppress the entire immune system because many cells within the immune system use the protein to mediate inflammatory responses to disease-causing microbes and thus protect us from infections.
Moreover, since reducing eosinophils seems to have the same effect on remodeling in both mice and humans, the results of Drs. Broide and Karin and their colleagues is strong evidence that mouse models of airway remodeling in asthma are both useful and meaningful for the study of the human disease.
Airway Remodeling in Humans and Mice
Several studies in mice and humans have previously indicated that both the NF-ĸB protein and eosinophils are involved in airway remodeling:
- Mice deficient in the cytokine interleukin 5 (IL-5) have significantly reduced levels of eosinophilic airway inflammation and reduced gene expression of the growth factor TGF-β1 after antigen challenge. They also have less airway remodeling.
- Human bronchial biopsies from people with mild chronic asthma who have been treated with an IL-5 antibody have reduced levels of eosinophils in their airways, reduced expression of the gene for TGF-β1, and fewer extracellular matrix proteins deposited during remodeling compared with bronchial biopsies taken from people with asthma who are not treated with the antibody.
- Mice that have either an inactivated subunit of the NF-ĸB protein or are treated with inhibitors of the complete protein do not exhibit airway eosinophilic inflammation.
- Human bronchial biopsies from people with asthma contain higher levels of one of the subunits of the NF-ĸB protein compared with lung tissue biopsies taken from people without asthma.
|
—Jason Bardi
The authors add that they would like to use the same mice deficient in NF-ĸB in bronchial tubes to study other diseases of the airways, such as chronic obstructive pulmonary disease.
Reference
Broide, D. et al. Allergen-induced peribronchial fibrosis and mucus production mediated by IĸB kinase β-dependent genes in airway epithelium. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0509235102 (2005).
back to top