Investigators: Alexander Larcombe, Emily Chivers
External collaborators: Professor Peter Henry (University of Western Australia)
Plain language summary: Patients with obstructive airway diseases such as asthma have difficulty breathing because their airway tubes are narrowed. Airway narrowing can be caused by excessive amounts of sticky mucus blocking the airway tube. Our project will use new techniques developed in our laboratories to investigate whether a group of medicines called “macrolides” can prevent the excessive production and release of mucus in the airways, and thus be beneficial in treating obstructive airway diseases.
Project description:
Chronic mucus hypersecretion is a pathologic feature of many airway disorders, including chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis and bronchiectasis. Currently, there are no specific effective pharmacotherapies for chronic mucus hypersecretion.
The principal aim of the project is to evaluate the effects of macrolides, a putative class of mucoregulatory drugs, on the distinct processes of mucin synthesis (Aim 1) and mucin secretion (Aim 2) in airways. These studies will use a novel ex vivo airway explant system recently developed in our laboratories, and be supported by complementary studies investigating the effects of macrolides on mucus production in established murine models of airways disease. The significance of the work extends beyond evaluating the effects of macrolides on mucus hypersecretion in biologically relevant systems. Additional studies will be undertaken to determine the effects of macrolides on normal mucus production, which plays a vital physiologic role in protecting the airways and the host from inhaled pathogens, pollutants and allergens (Aim 3).
Our novel ex vivo airway explant system together with in vivo experiments will be used to establish whether influenza A virus infection, which is influenced by the presence or absence of a functioning mucus, is affected by macrolides. Understanding whether macrolides are a “magic bullet” that suppresses mucus hypersecretion but not normal mucus production, or a “double-edged sword” that inhibits both mucus hypersecretion and normal mucus production will inform strategies on the use of macrolides for the management of hypersecretory disorders of the airways.