Protein linked to airway obstruction in asthma provides a potential treatment target

Researchers at National Jewish Health and colleagues have identified a mechanism involved in the formation of mucus plugs in asthma. Mucus plugs are thick, sticky accumulations of mucus that can form in asthma patients resulting in the blockage of airways. The researchers identified a protein involved in the generation of pathologic mucus present in plugs, which is a prominent feature of the disease in patients with type 2 inflammatory asthma.

The knowledge of this protein provides researchers with a potential new drug target for mucus obstruction in asthma patients. The study was published in the journal Nature Communications.

In patients with a subtype of asthma called type-2 (T2 high asthma), mucus plugs can block airflow and cause coughing, wheezing, and shortness of breath. “The T2 inflammation activated in many asthma patients, triggers their airway cells to secrete different protein products that can alter the molecular structure of mucus, ” said Max A. Seibold, Ph.D., director of the Regenerative Medicine and Genome Editing Program at National Jewish Health.

“These changes in the molecular structure of mucus also alter its physical properties, making these mucus secretions sticky, viscous, and difficult for patients to clear from their airways.”

The mechanism behind the formation of these airway mucus plugs, is poorly understood. In this study, researchers focused on a specific protein, intelectin-1, which is known to appear in these mucus plugs, to determine whether it plays a role in mucus plug formation.

For the study, investigators initially used lung airway cells from the National Jewish Health Live Cell Core, a biorepository of lung tissue for use in research studies. These lung cells were used to create a cellular model of T2 inflammation and explore the role of intelectin-1 in airway mucus formation. They found intelectin-1 was a key component of mucus produced by airway cells under the influence of T2 inflammation.

Airway cells normally move the mucus they produce through the beating of cilia on the surface of these cells. The researchers found that T2 mucus containing intelectin-1 was not moved well by airway cells. To test whether the intelectin-1 protein was contributing to the poor movement of T2 mucus, they genetically engineered cells to not produce the intelectin-1 protein. They found much of the loss in the movement of T2 mucus was restored by deleting the intelectin-1 gene. Moreover, they found the intelectin-1 protein bound to a key structural component of the mucus.

“The gene deletion studies strongly suggest that the intelectin-1 protein is involved in mucus obstruction among patients with T2-asthma,” according to Jamie Everman, MD, the first author of this work.

The researchers then screened a large cohort of asthma patients with airway cells for genetic variants in the intelectin-1 gene. They discovered a genetic variant in the intelectin-1 gene that results in low levels of intelectin-1 protein production from airway cells, and then tested whether carrying the intelectin-1 genetic variant was associated with the formation of mucus plugs. This investigation found that while T2-high patients without the genetic variant were at higher risk of airway mucus plug formation, those with the intelectin-1 genetic variant were protected from mucus plug formation.

“Through rigorous human translational research, we were able to identify a new, potentially targetable pathway for asthmatic mucus obstruction,” said Dr. Seibold. Going forward, Drs. Seibold and Everman plan to continue their investigation of intelectin-1 involvement in mucus obstructions and to develop asthma treatments that can inhibit the function of intelectin-1.

Researchers at National Jewish Health and colleagues have identified a mechanism involved in the formation of mucus plugs in asthma. Mucus plugs are thick, sticky accumulations of mucus that can form in asthma patients resulting in the blockage of airways. The researchers identified a protein involved in the generation of pathologic mucus present in plugs, which is a prominent feature of the disease in patients with type 2 inflammatory asthma.

The knowledge of this protein provides researchers with a potential new drug target for mucus obstruction in asthma patients. The study was published in the journal Nature Communications.

In patients with a subtype of asthma called type-2 (T2 high asthma), mucus plugs can block airflow and cause coughing, wheezing, and shortness of breath. “The T2 inflammation activated in many asthma patients, triggers their airway cells to secrete different protein products that can alter the molecular structure of mucus, ” said Max A. Seibold, Ph.D., director of the Regenerative Medicine and Genome Editing Program at National Jewish Health.

“These changes in the molecular structure of mucus also alter its physical properties, making these mucus secretions sticky, viscous, and difficult for patients to clear from their airways.”

The mechanism behind the formation of these airway mucus plugs, is poorly understood. In this study, researchers focused on a specific protein, intelectin-1, which is known to appear in these mucus plugs, to determine whether it plays a role in mucus plug formation.

For the study, investigators initially used lung airway cells from the National Jewish Health Live Cell Core, a biorepository of lung tissue for use in research studies. These lung cells were used to create a cellular model of T2 inflammation and explore the role of intelectin-1 in airway mucus formation. They found intelectin-1 was a key component of mucus produced by airway cells under the influence of T2 inflammation.

Airway cells normally move the mucus they produce through the beating of cilia on the surface of these cells. The researchers found that T2 mucus containing intelectin-1 was not moved well by airway cells. To test whether the intelectin-1 protein was contributing to the poor movement of T2 mucus, they genetically engineered cells to not produce the intelectin-1 protein. They found much of the loss in the movement of T2 mucus was restored by deleting the intelectin-1 gene. Moreover, they found the intelectin-1 protein bound to a key structural component of the mucus.

“The gene deletion studies strongly suggest that the intelectin-1 protein is involved in mucus obstruction among patients with T2-asthma,” according to Jamie Everman, MD, the first author of this work.

The researchers then screened a large cohort of asthma patients with airway cells for genetic variants in the intelectin-1 gene. They discovered a genetic variant in the intelectin-1 gene that results in low levels of intelectin-1 protein production from airway cells, and then tested whether carrying the intelectin-1 genetic variant was associated with the formation of mucus plugs. This investigation found that while T2-high patients without the genetic variant were at higher risk of airway mucus plug formation, those with the intelectin-1 genetic variant were protected from mucus plug formation.

“Through rigorous human translational research, we were able to identify a new, potentially targetable pathway for asthmatic mucus obstruction,” said Dr. Seibold. Going forward, Drs. Seibold and Everman plan to continue their investigation of intelectin-1 involvement in mucus obstructions and to develop asthma treatments that can inhibit the function of intelectin-1.