Scientists at King’s College London have discovered a new cause of asthma, raising hopes of finding a treatment that could prevent the potentially deadly disease.
Most current treatments for asthma are based on the idea that it is an inflammatory disease. However, the life-threatening feature of asthma is the attack or constriction of the airways, making it difficult to breathe. The new study, published today in Scienceshows for the first time that many features of an asthma attack (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 normally causes epithelial cell death could prevent the damage, inflammation and mucus that result from an asthma attack.
Professor Jody Rosenblatt from King’s College London said: “Our discovery is the culmination of more than ten years of work. As cell biologists observing the processes, we could 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 suffer from long-term inflammation, wound healing and infections that cause 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 and can suffer symptoms such as wheezing, coughing, feeling short of breath and tightness in the chest. Triggers such as pollen or dust can worsen asthma symptoms and lead to a life-threatening asthma attack.
Although the diseases are common, the causes of asthma are still not understood. Current medications treat the consequences of an asthma attack by opening the airways, calming inflammation, and breaking up the sticky mucus that blocks the airways, which helps control asthma, but does not prevent it.
The answer to stopping asthma symptoms may lie in cell extrusion, a process that researchers found drives most epithelial cell death. Scientists used mouse lung models and human airway tissue to discover that when the airways constrict, known as bronchoconstriction, the epithelial cells lining the airways are expelled and then die.
Because bronchoconstriction causes so many cell extrusions, it damages the airway barrier, causing 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 excess 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 considered safe or effective.
Professor Rosenblatt said: “This constriction and destruction of the airways causes post-attack inflammation and excess mucus secretion which makes it difficult for people with asthma to breathe.
“Current therapies do not prevent this destruction: an inhaler like Albuterol opens the airways, which is essential for breathing, but unfortunately, we found that it does not prevent the damage or symptoms that follow an attack. Fortunately, we found that An inexpensive compound, gadolinium, which is frequently used in magnetic resonance imaging, can be used to stop airway damage in mouse models, as well as the resulting inflammation and secretion of mucus. Preventing this damage could prevent the buildup muscle that causes future attacks.”
Professor Chris Brightling from the University of Leicester and one of the study’s co-authors said: “Over the last decade there has been enormous progress in asthma therapies targeting particularly airway inflammation. However, symptoms persist. and attacks in many people with asthma. This study identifies a new process known as epithelial extrusion by which damage to the lining of the airways occurs as a consequence of mechanical constriction and may drive many of the key features of asthma. It is likely that “A better understanding of this process will lead to new therapies for asthma.”
Dr Samantha Walker, Director of Research and Innovation at Asthma + Lung UK, said: “Only two per cent of public health funding is allocated to developing new treatments for the 12 million people living with lung diseases. in the UK, so new research that may help in the treatment or prevention of asthma is good news.
“This research using an experimental mouse model shows that constriction of the airways causes damage to the lining of the lungs and inflammation, such as that seen in asthma. It is this constriction and the resulting damage that makes it difficult to breathe of people with asthma.
“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 ~31 percent of People with asthma do not use inhalers. They don’t have treatment options that work for them, putting them at risk for life-threatening asthma attacks.
“This discovery opens important new doors to explore potential new treatment options that people with asthma desperately need, rather than focusing solely on inflammation.”
Discovering the mechanics behind cell extrusion could underlie other inflammatory diseases that also feature constriction, such as intestinal cramps and inflammatory bowel disease.
The paper is done in collaboration with the University of Leicester and is funded by Wellcome, the Howard Hughes Medical Institute and the American Asthma Foundation.