Airway Inflammation and Airway Remodeling in Severe Asthma

Airway remodeling is the term applied to the structural changes observed in the airway in asthma, and includes
an increase in airway wall thickness which is associated with an increase in airway smooth muscle (ASM)
mass, sub-epithelial fibrosis, mucus metaplasia of epithelial cells, abnormalities in composition of the
extracellular matrix, and an increase in peribronchial vascularity. Although current NIH guidelines recommend
maintaining a goal of normal lung function in asthma, current therapeutic strategies in asthma are not able to
specifically target airway remodeling as the cellular and molecular mechanisms that result in remodeling are
not well defined. Studies have also demonstrated that severe asthmatics with increased ASM on
endobronchial biopsy have lower lung function (FEV1) compared to asthmatics with less ASM. Thus, ASM
remodeling may contribute significantly to lower FEV1 in severe asthma. Although severe asthmatics
comprise only approximately 5% of all asthmatics, they utilize a significant amount of health care resources
(approximately 40% of the estimated $50 billion direct costs of asthma/year in the USA). As airway remodeling
in severe asthma can contribute to lower lung function and a greater decline in lung function, there is an
important need to identify mechanisms by which airway remodeling is mediated so that potential novel
therapies could be directed at these pathways. The UCSD AADCRC will test the hypothesis that novel non-
TH2-based inflammatory pathways in immune cells, inflammatory cells and epithelial cells mediate airway
remodeling in severe asthma. In support of this overall hypothesis, Project 1 (Broide) has identified that
Gasdermin A (GSDMA) is expressed at increased levels in epithelial cells in asthma, inhibits antiviral defense
pathways in epithelium, which can trigger severe RV-induced asthma exacerbations with decline in lung
function and airway remodeling. Project 2 (Croft) has identified that TNF family members LIGHT and TL1A
(both increased expression in severe asthma) can directly induce human ASM and fibroblast remodeling
underscoring the importance of this pathway to remodeling in severe asthma. Project 3 (Vijayanand) has
identified increased frequency of a novel T cell population (i.e. cytotoxic TRM cells) in the airways of severe
asthmatics, which may help to explain persistent T cell-driven inflammation and airway remodeling not due to
known T cell populations (TH2 or TH1). We anticipate that each of the thee projects will identify selective
pathways to airway remodeling, as well as shared pathways to remodeling that we have identified related to
TRM cells, LIGHT/TL1A, and GSDMA. Novel pathways inducing airway remodeling in severe asthma will be
tested in each project using human airway structural cells and TRM cells obtained by BAL, brushing, and
endobronchial biopsy by “Severe Asthma Clinical Core B” from severe asthmatics and controls (mild asthma;
non-asthma). Overall, these studies will identify potential novel therapeutic targets to inhibit airway remodeling
and prevent decline in lung function in severe asthma.

Grant Number: 3U19AI070535-20S1
NIH Institute/Center: NIH
Principal Investigator: DAVID BROIDE