SWEHSC researchers’ findings indicate potential asthma treatment
C781 targets allergen-induced inflammation
In a recent publication involving SWEHSC members Drs. Scott Boitano and Julie Ledford, researchers tested a compound, C781, to see how effective it is as a targeted approach that addresses allergen-induced symptoms in an animal model. C781 was developed through testing on human cells from the air passages that lead to and through the lungs (bronchial tubes) before being tested in mice for allergen-induced asthma. These tests indicate C781 is an effective treatment for allergen-induced asthma-like symptoms in the airway.
What were their key findings?
In animal models, C781 helps improve allergen-induced symptoms by reducing airway hyperresponsiveness, inflammation, and mucus overproduction in the lungs and airway that underlie the breathing difficulties associated with asthma. C781 is exciting because it targets a novel signaling pathway that leaves other immune responses unaffected. This is beneficial because it can help prevent unwanted side effects, like tremor or nausea, which are common side effects of currently used medications.
What is asthma?
Asthma is a chronic lung disease that includes obstruction of air flow, inflammation, and muscle tightness in the airway. It is one of the most common respiratory diseases in the United States, with about 1 in 12 people diagnosed 1. Asthma development in a person can be influenced by genetics, environmental allergens, history of respiratory infections and exposure to chemical irritants. Asthma is classified as mild, moderate or severe, with severe asthma attacks potentially being fatal. Symptoms of asthma may include coughing, wheezing, shortness of breath, and a tight or crushing feeling in the chest. Because there is a wide range of symptoms and genetic factors contributing to asthma, it is challenging to develop effective targeted treatments.
How do we currently treat asthma?
Current treatments for asthma primarily focus on relieving symptoms by reducing airway inflammation. Common medications include β-adrenergic agonists and corticosteroids (which are usually inhaled into the airway and lungs using an inhaler). These medications reduce inflammation and tightness in the airways and make it easier to breathe. However, they can also cause side effects like nausea, tremors, dizziness, headache and tachycardia (a heart rate over 100 beats per minute). Newer medications, or “biologics,” are typically injected and are targeted to a subset of asthma patients. As such, researchers are always looking to improve new medications to expand treatment options and limit undesirable side effects.
How does PAR2 affect the asthma response?
Cells in human lungs have receptors called proteinase-activated receptor-2 (PAR2). When activated by a protease-containing allergen (including certain fungi, cockroach frass or house dust mites), PAR2 receptors in airway cells send a message along their signaling pathways to initiate an inflammatory response that results in airway sensitivity, swelling and constriction. Current asthma medications target the results of PAR2 signaling, but there are no asthma medications that target PAR2.
Why target only a portion of the PAR2 response?
While fully inhibiting PAR2 decreases airway inflammatory associated signaling pathways, it also inhibits signaling pathways independent of these effects. Specifically, while the β-arrestin/MAPK signaling pathway of PAR2 increases airway inflammatory responses, the Gq/Ca2+ signaling pathway actually helps open airways through bronchial relaxation, making it easier to breathe. Because some of the unwanted side effects stem from this second pathway being shut down, if a medication could target just the airway inflammatory response, it could also lead to reduced side effects. The goal of this study was to assess how effective C781 is at targeting and preventing inflammatory signal associated with PAR2 signals without impacting its beneficial signaling pathways.
What are the benefits of C781?
Study results showed that mice nasally inoculated with C781 had reduced airway hyperresponsiveness, inflammation, and mucus production in response to an allergen challenge. This response occurred because C781 blocked the inflammatory signals from allergen-induced PAR2 activation. Researchers found that C781 had no significant effect on the other pathway that prompts the airways to relax, allowing for increased airflow.
What comes next?
Although this experiment involved mouse models and human bronchial cells, it has not yet been tested in humans in a clinical trial. The researchers in this study believe C781 shows promise for its anti-inflammatory capabilities, and that further research could one day lead to C781 treatment in human asthma patients.
To learn more, read the full research article.