Integrative Roles of Pro‐Inflammatory Cytokines on Airway Smooth Muscle Structure and Function in Asthma

Abstract

ABSTRACTAsthma has become more appreciated for its heterogeneity with studies identifying type 2 and non‐type 2 phenotypes/endotypes that ultimately lead to airflow obstruction, airway hyperresponsiveness, and remodeling. The pro‐inflammatory environment in asthma influences airway smooth muscle (ASM) structure and function. ASM has a vast repertoire of inflammatory receptors that, upon activation, contribute to prominent features in asthma, notably immune cell recruitment and activation, hypercontractility, proliferation, migration, and extracellular matrix protein deposition. These pro‐inflammatory responses in ASM can be mediated by both type 2 (e.g., IL‐4, IL‐13, and TSLP) and non‐type 2 (e.g., TNFα, IFNγ, IL‐17A, and TGFβ) cytokines, highlighting roles for ASM in type 2 and non‐type 2 asthma phenotypes/endotypes. In recent years, there has been considerable advances in understanding how pro‐inflammatory cytokines promote ASM dysfunction and impair responsiveness to asthma therapy, corticosteroids and long‐acting β2‐adrenergic receptor agonists (LABAs). Transcriptomic analyses on human ASM cells and tissues have expanded our knowledge in this area but have also raised new questions regarding ASM and its role in asthma. In this review, we discuss how pro‐inflammatory cytokines, corticosteroids, and LABAs affect ASM structure and function, with particular focus on changes in gene expression and transcriptional programs in type 2 and non‐type 2 asthma.