WNT signaling in airway remodeling in asthma: novel roles for WNT-5A in airway smooth muscle

Asthma is a chronic obstructive respiratory disease that afflicts millions of people worldwide. A number of both genetic and environmental factors may contribute to asthma. Structural changes in the airways, known as airway remodeling, is a crucial pathological feature of asthma which may lead to lung function decline in severe disease. Little is known about the factors and mechanisms that drive airway remodeling and there are no curative or management interventions available for airway remodeling. This thesis investigates the molecular mechanisms involved in airway remodeling with a particular focus on WNT signaling.
WNT signaling is involved in development of organs including the lungs and is also implicated in several diseases such as cancer and fibrosis. We investigated the role of WNT signaling in regulating the features of airway remodeling. Using airway smooth muscles obtained from asthma patients, we found that WNT-5A, a WNT protein, is highly increased in these cells. Further investigation revealed that WNT-5A regulates the expression of extracellular matrix and contractile proteins in airway smooth muscle cells. An altered profile of extracellular matrix and contractile proteins is a feature of remodeled airways in asthma subjects. Using a mouse model of chronic allergen induced airway inflammation, we found that WNT signaling is extensively modulated in the lungs. Of note, a WNT pathway inhibitor, WNT inhibitory factor 1 was found reduced in the lungs of allergen challenged animals.
This thesis unravels several molecular pathways and factors involved in WNT mediated airway remodeling in asthma and provides several potential targets that can be utilized for therapeutic intervention.