Airway Structural Cells and Corticosteroid Resistance in Asthma

PROJECT SUMMARY
Asthma remains a significant healthcare burden for children and has a long-term impact on their
development and health. Inhaled corticosteroids are key for managing asthmatic symptoms and disease
progression. However, children with severe asthma are insensitive or resistant corticosteroid therapies, leading
to the need for systemic use at high doses. Airway smooth muscle (ASM) is a key structural cell that regulates
airway function and tone. In severe pediatric asthma, airway inflammation, hyperresponsiveness (AHR), and
remodeling continues despite aggressive corticosteroid treatments. Yet the underlying biological mechanisms of
corticosteroid insensitivity or resistance, particularly in ASM, remain undefined. Studies have reported
associations between Th1 inflammation, as indicated by increased Th1 lymphocyte airway infiltration and IFNγ
levels, and severe asthma. Additionally, we recently showed that combined exposure to IFNγ and TNFα uniquely
induces corticosteroid resistance in ASM. These data have led us to hypothesize that IFNγ and TNFα interactions
enable pro-inflammatory signaling pathways, notably NFκB and JAK/Stat1, to remain activated in the presence
of corticosteroids. Via 2 Specific Aims, we will use novel mouse and human models of corticosteroid resistance
to examine airway inflammation, hyperresponsiveness (AHR), and remodeling in ASM. Specific Aim 1 will test
the hypothesis that IFNγ enhances airway hyperresponsiveness and remodeling in ASM during steroid resistant
allergic airway inflammation. While Specific Aim 2 will test the hypothesis that combined exposure to IFNγ and
TNFα opens chromatin structure, leading to corticosteroid resistance in human pediatric ASM. This proposal will
involve using cellular, molecular, and bioinformatic approaches to understand how interactions between IFNγ
and TNFα enhance Ca2+ regulatory mechanisms and transcriptional regulation in ASM. Furthermore, we will
examine whether targeting the JAK/Stat pathway can improve corticosteroid sensitivity in ASM and improve
airway function. These novel studies will expand the current understanding of how airway structural cells, such
as ASM, develop corticosteroid resistance while also beginning to define mechanisms that mediate corticosteroid
resistance in severe pediatric asthma.

Grant Number: 5R01HL155095-05
NIH Institute/Center: NIH
Principal Investigator: Rodney Britt