A promising asthma treatment proved to be successful in early trials on mice
It is estimated that more than 250 million people globally suffer from asthma, which also causes hundreds of thousands of fatalities annually. Therefore, finding a cure for the condition could be life-changing for a large number of people.
Scientists have now developed a new potential long-term treatment for asthma. The method, which not only treats the symptoms of asthma but also targets one of its causes, functions by preventing the mobility of a certain kind of stem cell known as a pericyte.
Pericytes are mostly found in the lining of blood vessels, and they are known to thicken the airways of people with asthma when an allergic and inflammatory reaction occurs, making breathing more challenging.
"By targeting the changes in the airway directly, we hope this approach could eventually offer a more permanent and effective treatment than those already available, particularly for severe asthmatics who don't respond to steroids," says biologist and pharmacologist Jill Johnson from Aston University in the U.K.
When the airways become thickened, shortness of breath and wheezing can be seen in people with asthma. In this case, steroids can help people by relaxing the airways and reducing the risk of inflammation. This, however, is not a permanent solution.
Thinning the airway walls
Preventing pericytes from reaching the airway walls could impact one of the underlying causes of shortness of breath. So the researchers targeted a protein called CXCL12 to get at the pericytes. In their experiments on mice with asthma, researchers have found that inhibiting the signal from this protein resulted in a week-long decrease in symptoms and a two-week eradication of all asthmatic symptoms.
"We were able to mitigate pericyte uncoupling from the airway microvasculature, resulting in decreased airway smooth muscle accumulation and improved symptom scores," wrote the researchers in the study paper.
When compared with control mice, the mice who received the treatment had thinned airway walls. This is particularly promising in terms of the treatment's efficacy, which scientists also tested on lab-grown human tissue cells.
Even though the research is exciting for the development of a treatment for such a condition that affects so many people globally, there's still a long way to go before being available as a treatment.
"Our work is still at an early stage, and further research is needed before we can begin to test this in people," states Johnson.
The results of the study were published in the journal Respiratory Medicine.
Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation.
Mice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro.
Pericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927.
These results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation.
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