Scientists at King’s College London have discovered a new cause of asthma, raising hopes for a treatment that could prevent this potentially life-threatening disease.
Asthma, a common airway disorder, is typically understood as a condition of excessive inflammation in which environmental triggers stimulate immune responses in the lungs, leading to bronchoconstriction. The mainstays of asthma treatment are albuterol, a short-acting bronchodilator for immediate symptom relief, and corticosteroids to address the underlying inflammation. Unfortunately, this approach is not always effective, even when used in combination. Bagley and colleagues have demonstrated that mechanical damage to the airways caused by bronchoconstriction and the extrusion of epithelial cells also contributes to asthma pathology and may interfere with healing (see Perspective by Drazen and Fredberg). Conversely, compounds that counteract this mechanical damage showed beneficial effects in mouse models, either alone or in combination with albuterol, though their safety in humans remains to be evaluated. —Yevgeniya Nusinovich
Most current asthma treatments are based on the idea that it is an inflammatory disease. However, the life-threatening characteristic of asthma is the attack or constriction of the airways, which makes breathing difficult. The new study, published in Science, shows for the first time that many features of an asthma attack—such as inflammation, mucus secretion, and damage to the airway barrier that prevents infections—are the result of this mechanical constriction in a mouse model.
The findings suggest that blocking a process that typically causes epithelial cell death could prevent the damage, inflammation, and mucus production that result from an asthma attack.
Professor Jody Rosenblatt of King’s College London stated: "Our discovery is the culmination of over ten years of work. As cell biologists observing these processes, we were able to see that the physical constriction of an asthma attack causes widespread destruction of the airway barrier. Without this barrier, asthma patients are much more likely to experience long-term inflammation, wound scarring, and infections that lead to more attacks. By understanding this fundamental mechanism, we are now in a better position to prevent all these events."
In the UK, 5.4 million people suffer from asthma, experiencing symptoms such as wheezing, coughing, shortness of breath, and chest tightness. Triggers such as pollen or dust can worsen asthma symptoms and lead to a potentially fatal asthma attack.
Despite the common nature of the disease, the causes of asthma remain poorly understood. Current medications treat the consequences of an asthma attack by opening the airways, calming inflammation, and breaking up sticky mucus that clogs the airways, which helps manage asthma but does not prevent it.
The answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers found to drive much of the epithelial cell death. Using mouse lung models and human airway tissue, the scientists discovered that when the airways contract, known as bronchoconstriction, the epithelial cells lining the airways are expelled and subsequently die.
Because bronchoconstriction causes so much cell extrusion, it damages the airway barrier, leading to inflammation and excess mucus. In previous studies, scientists found that the chemical compound gadolinium can block extrusion. In this study, they found that it could work in mice to prevent excessive extrusion that causes damage and inflammation after an asthma attack. The authors note that gadolinium has not been tested in humans and has not been deemed safe or effective.
Professor Rosenblatt said: "This constriction and destruction of the airways lead to post-attack inflammation and excess mucus secretion, which make it difficult for people with asthma to breathe.
"Current therapies do not prevent this destruction: an inhaler like albuterol opens the airways, which is crucial for breathing, but unfortunately, we found that it does not prevent the damage or symptoms that follow an attack. Fortunately, we discovered that an inexpensive compound, gadolinium, frequently used in MRI imaging, can stop airway damage in mouse models, as well as the subsequent inflammation and mucus secretion. Preventing this damage could prevent the buildup of muscle that leads to future attacks."
Professor Chris Brightling from the University of Leicester, and one of the study’s co-authors, said: "In the past decade, there has been enormous progress in asthma therapies, particularly those targeting airway inflammation. However, symptoms and attacks persist in many people with asthma. This study identifies a new process known as epithelial extrusion, through which damage to the airway lining occurs as a result of mechanical constriction and may drive many key characteristics of asthma. A better understanding of this process is likely to lead to new therapies for asthma."
Dr. Samantha Walker, Director of Research and Innovation at Asthma + Lung UK, said: "Only 2% of public health funding is allocated to the development of new treatments for the 12 million people living with lung disease in the UK, so new research that can help treat or prevent asthma is good news.
"This research, using an experimental mouse model, shows that airway constriction causes lung lining damage and inflammation, similar to what is seen in asthma. It is this constriction and the resulting damage that makes it difficult for people with asthma to breathe.
"Current asthma medications work by treating inflammation, but this is not effective for everyone. Treatments aim to prevent future asthma attacks and improve asthma control by taking inhalers every day, but we know that around 31% of people with asthma do not have treatment options that work for them, putting them at risk of potentially fatal asthma attacks.
"This discovery opens important new doors for exploring possible new treatment options that people with asthma urgently need, instead of focusing solely on inflammation."
The discovery of the mechanics behind cell extrusion could serve as a foundation for other inflammatory diseases that also involve constriction, such as intestinal cramps and inflammatory bowel disease.
The article was produced in collaboration with the University of Leicester and is funded by Wellcome, the Howard Hughes Medical Institute, and the American Asthma Foundation.
