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Asthma affects around 260 million people worldwide, making it one of the most common chronic respiratory conditions. Despite advances in treatment, it still contributes to hundreds of thousands of deaths each year: in 2019, approximately 461,000 people died from asthma. Beyond the immediate risk of fatal asthma attacks, the disease also leaves behind lasting scars. Severe asthma causes structural changes in the lungs known as airway remodelling, stiffening, and scarring of tissue, often thought to be irreversible.
Current therapies focus largely on reducing inflammation but for many patients, that is not enough to prevent irreversible damage to the lung structure. A new study led by the University of Aberdeen and collaborators at the University of Manchester explores a different path: targeting molecular drivers of scarring. The researchers focused on a family of proteins, chitinase-like proteins, already observed at elevated levels in people with asthma, and tested whether blocking them in mice could reverse tissue damage.
“When we blocked chitinase-like proteins in mice, we were able to reverse some of the damage,” said Dr. Tara Sutherland, lead researcher of the study at the University of Aberdeen. “This suggests a potential new way to treat disease in some types of asthma, possibly alongside the use of anti-inflammatory therapy.”
While promising, the findings are based on animal models and must still be validated in human tissues. But they hint at a future where asthma treatment could go beyond suppression of inflammation to repair of lung injury.
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Current state of asthma treatment
For decades, the standard of care in asthma has revolved around inhaled corticosteroids (ICS) and bronchodilators, with more severe cases receiving systemic steroids or biologics targeting specific inflammatory pathways. “Current asthma treatments like steroid inhalers and biologics primarily target inflammation. These work very well for many people with asthma, but some people with severe asthma don’t respond to them,” said Sutherland.
Indeed, a nontrivial subset of asthma sufferers, particularly those with severe or steroid-insensitive asthma, get limited benefit from these therapies. Some patients remain uncontrolled despite optimal anti-inflammatory regimens, continuing to suffer symptoms, recurrent exacerbations, and decline in lung function.
“In terms of asthma progression, for some people with severe disease, simply treating inflammation may not be enough to reverse the scarring in the lungs. As a result, people might continue to have symptoms even if inflammation is well controlled,” said Sutherland. Over time, asthma can cause airway remodeling, increased collagen deposits, fibrosis, smooth muscle hypertrophy, mucus gland enlargement, and stiffening of tissues. These changes reduce elasticity, contribute to fixed airflow limitation, and may persist even when inflammation is well controlled.
“We still need to learn more about how this scarring develops and exactly how it shapes the course of asthma, but it does highlight the need for treatments that go beyond just targeting inflammation,” added Sutherland. And finding new solutions to potentially reverse lung scarring is exactly what she is trying to achieve with her team.
The discovery: Can we reverse lung scarring?
Asthma researchers have long suspected that molecules beyond canonical inflammatory mediators play a role in structural lung changes. Among these, chitinase-like proteins (CLPs) have drawn attention. These proteins do not enzymatically break down chitin, as true chitinases do, but they bind chitin and may have roles in inflammation, tissue remodeling, and fibrosis.
In people with asthma, particularly severe forms, levels of certain CLPs correlate with disease severity. For example, YKL-40 has been found at elevated levels in serum and lung tissue, with associations to airway thickening, exacerbation risk, and reduced responsiveness to standard treatments. These observations have long begged the question: are CLPs passive biomarkers, or are they active drivers of disease progression and structural damage?
“The more of these proteins someone has, the more severe their asthma tends to be. That’s why we wanted to study them, to better understand how they contribute to the disease and whether they could be a useful target for treatment,” said Sutherland.
The Aberdeen-Manchester team turned that question into an experiment. In mouse models designed to mimic severe, steroid-insensitive asthma, they exposed mice to allergens to induce chronic airway inflammation, structural remodeling, and lung damage analogous to human severe asthma. “Crucially, these mice also don’t respond to steroid treatment, just like many patients with severe asthma who are steroid-insensitive. That makes them a valuable tool for studying new treatment approaches, which we can then go on to explore in human cells and tissues,” explained Sutherland.
When the researchers blocked chitinase-like proteins in these mice, they observed partial reversal of lung scarring, stiffness, and structural damage. This finding suggests that structural changes once thought only preventable might be reparable.
However, this is still animal-only work. No human data is yet available, and many biological differences remain between mice and people, especially regarding lung architecture, immune regulation, and repair processes. Moreover, the precise molecular mechanism by which CLP inhibition triggers reversal of fibrosis is not fully delineated. The authors themselves caution that much work is needed to validate these findings in human tissues, develop safe inhibitors, and explore dosage, side effects, and delivery.
From mice to patients: Why this might matter beyond asthma
To translate the Aberdeen-Manchester findings into a therapy, researchers will need to develop inhibitors against the human chitinase-like proteins implicated in scarring and then test them in human cells and lung tissue. As Sutherland notes, this is a high bar because studying structural changes generally requires access to lung tissue and advanced imaging: “One of the challenges is that studying structural changes in the lung requires actual lung samples, which are much more difficult and challenging to obtain than blood cells.” In asthma, the gold standard for assessing airway remodeling remains bronchial biopsy, while computed tomography (CT) and newer MRI techniques are increasingly used as non-invasive complements to track wall thickening, airway smooth-muscle mass, and matrix changes.
Even with the right tools, drug development timelines are long. As Sutherland put it plainly: “Realistically, we are looking at least a decade before this could potentially translate into therapies.” Peer-reviewed benchmarking of development times supports that order of magnitude.
Why invest that effort? Airway remodeling drives symptoms and fixed airflow limitation in a subset of patients, and is not addressed by today’s anti-inflammatory standards of care. Non-invasive imaging can visualize elements of this remodeling, but reversing it remains an unmet need for steroid-insensitive severe asthma.
The broader relevance depends on whether CLPs are drivers of fibrosis across organs or mainly biomarkers. There’s evidence that CLPs, particularly CHI3L1/YKL-40, are elevated in a range of fibrotic and remodeling-heavy diseases, from chronic obstructive pulmonary disease (COPD) and other chronic lung conditions to liver fibrosis and cardiovascular disease.
Still, causality and therapeutic tractability must be proven disease by disease. As Sutherland cautioned, “We still need to understand exactly how they drive or resolve fibrosis, and that’s something we’re actively working on. If the mechanisms turn out to be similar across different tissues and disease states, there’s real potential to explore inhibitors of these proteins in conditions like COPD, heart disease, or cirrhosis. But the first step is to build the fundamental knowledge before we can move toward treatments.”
Challenges and opportunities ahead
Turning this discovery into a therapy faces major hurdles. “Studying blood cells is difficult but more straightforward; studying structural changes in the lungs is much harder. It typically requires lung biopsies or new advanced imaging technologies, which take time to develop and make widely available,” said Sutherland. Beyond the science, funding remains a persistent challenge, with progress relying heavily on the support of charities and research councils.
Sutherland said there is some industry interest in chitinase-like proteins as potential drug targets, but much remains unknown about how they work. “Our study is part of that fundamental research; understanding what these molecules do and how they do it is essential before we can know if they’re a viable option for new therapies,” she added.
For now, the opportunity lies in reframing how asthma is studied, not only as an inflammatory condition but also as one marked by structural damage that could one day be reversed.
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