A preclinical study led by scientists at King’s College London, and at the University of Leicester, suggests that preventing the mechanical damage caused by an asthma attack, rather than treating the downstream symptoms, could pave the way for therapies that stop the whole asthma inflammatory cycle.
Most current asthma treatments stem from the concept that it is an inflammatory disease, yet the life-threatening feature of asthma is the attack, or the constriction of airways, making breathing difficult. The newly reported study using human tissue and in mice, has shown for the first time that many features of an asthma attack—inflammation, mucus secretion, and damage to the airway barrier that prevents infections – result from this mechanical constriction. The tightening of muscles around the bronchi causes damage to the airway by squeezing and destroying epithelial cells, and this then promotes the airway inflammation and mucus production that is associated with an asthma attack.
The new findings suggest that blocking the process that causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack. “In the last decade there has been tremendous progress in therapies for asthma particularly directed towards airway inflammation,” said Chris Brightling, PhD, at the University of Leicester. “However, there remains ongoing symptoms and attacks in many people with asthma. This study identifies a new process known as epithelial extrusion whereby damage to the lining of the airway occurs as a consequence of mechanical constriction and can drive many of the key features of asthma. Better understanding of this process is likely to lead to new therapies for asthma.”
Brightling and colleagues reported on their research in Science, in a paper titled “Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion.”
Asthma is a common airway disorder affecting more than 300 million people worldwide, the authors wrote. In the UK, 5.4 million people have asthma and can suffer from symptoms such as wheezing, coughing, feeling breathlessness and a tight chest. Triggers such as pollen or dust can make asthma symptoms worse and can lead to a life-threatening asthma attack.
Despite the disease commonality, 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 which clogs the airway, which help control asthma, but do not prevent it.
Although asthma is primarily considered an inflammatory disease, a diagnostic feature is mechanical bronchoconstriction – the constriction of the smooth muscle that surrounds the airway – which can result in severe breathing difficulty and increased airway mucus production. “Although diverse stimuli can trigger asthma attacks that cause different types of immune responses, the universal life-threatening pathology shared by asthmatics is mechanical bronchoconstriction,” the team stated.
Airway immune activation and inflammation are thought to drive bronchoconstriction during asthma exacerbations (acute episodes of worsening asthma symptoms). And as the authors noted, “After a severe exacerbation, patients with asthma frequently experience an extended period of airway inflammation for weeks to months that can predispose individuals to further attacks,”
The gold standard therapy for asthma exacerbations is albuterol, a short-acting bronchodilator, and inhaled corticosteroids, which treat the underlying inflammation. However, these treatments are not always effective, and a mechanistic understanding of asthma exacerbations remains incomplete. “… many patients continue to experience poor symptom control and airway hyperresponsiveness,” the investigators stated. “Thus, identifying other etiologies driving asthma morbidity and mortality is a priority.”
Building on previous research, first author Dustin Bagley, PhD, at Kings College, London, and colleagues investigated the underlying root causes of asthma pathobiology. Their newly reported study suggests that the answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers discovered that drives most epithelial cell death.
Using mouse models of asthma and human lung tissue samples, the team discovered that bronchoconstriction causes a pathological overcrowding of cells in the airway epithelium, triggering a process called cell extrusion that leads to airway tissue damage. When the airways contract the epithelial cells that line the airway get squeezed out to later die.
This mechanism, the studies demonstrated, resulted in inflammation and mucus secretion in both mice and humans. The damage then results in a breakdown of epithelial barrier function and could provide a pathway for further bronchoconstrictive attacks and inflammation.
Senior study author, Jody Rosenblatt, PhD, Professor of Cell Biology at King’s College London “This constriction and destruction of the airways causes the post-attack inflammation and excess mucus secretion that makes it difficult for people with asthma to breathe. Current therapies do not prevent this destruction – an inhaler such as albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack.
Although the authors demonstrated that albuterol treatment does not prevent airway epithelia damage or its resultant inflammation after an asthma attack, they found that inhibitors that stopped the cell extrusion pathway counteracted mechanical damage to the airway and substantially reduced the inflammatory response. In previous studies, they had shown that the chemical compound gadolinium (Gd3+) can block extrusion. In this study, they found it could work in mice to prevent the excess extrusion that causes damage and inflammation after an asthma attack.
“Albuterol treatment, routinely used by asthma patients for symptom relief of bronchospasm, does not prevent airway epithelia destruction, mucus secretion, or inflammation after an asthma attack,” the team stated in their paper. “However, blocking the extrusion pathway with gadolinium or S1P inhibitors after bronchoconstriction preserved epithelial integrity, substantially dampening the inflammatory response.”
Rosenblatt added, “Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks.”
The authors noted that gadolinium has not been tested in humans and has not been deemed to be safe or efficacious. Nevertheless, they wrote, “… Gd3+ has the advantage of generically blocking extrusion upstream in the extrusion pathway … Additionally, transient use of Gd3+ has the added benefit that it may be used practically once an attack occurs without apparent side effects in mice, but its safety will need to be tested in human airways.”
Rosenblatt stated, “Our discovery is the culmination of more than ten years work. As cell biologists who watch processes, we could see that the physical constriction of an asthma attack causes widespread destruction of the airway barrier. Without this barrier, asthma sufferers are far more likely to get 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.”
Samantha Walker, Director of Research and Innovation at Asthma + Lung UK, said, “Current medications for asthma work by treating the inflammation, but this isn’t effective for everyone … This discovery opens important new doors to explore possible new treatment options desperately needed for people with asthma rather than focusing solely on inflammation.”
In a related perspective Jeffery Drazen, PhD, and Jeffery Fredberg, PhD, at Harvard School of Public Health, stated, “It may be time for a renewed focus on airway mechanics as an avenue to prevent and treat exacerbations of asthma … These findings not only establish that bronchoconstriction is a pro-inflammatory stimulus but also point toward the potential for new research avenues that seek to inhibit a ‘mechano-inflammatory’ vicious cycle.”
The discovery of the mechanics behind cell extrusion could underlie other inflammatory diseases that also feature constriction such as cramping of the gut and inflammatory bowel disease. In their perspective, Drazen and Fredberg pointed out. “Such a mechanism helps to paint a more complete picture of asthma pathobiology and may be relevant to other conditions, such as irritable bowel syndrome, in which epithelial cells are subject to disruptive mechanical forces.”
