Dynamic Regulation of Collagens, Proteases, Their Inhibitors, and Cell Death in Experimental Asthma in Mice

ABSTRACT Asthma is a complex airway disorder driven by diverse immunological pathways. While type 2 (T2)‐mediated inflammation is well characterized, the mechanisms underlying T2‐low (also referred to as mixed inflammatory phenotype) or non‐T2‐mediated asthma, often associated with Th1/Th17‐driven immune responses and high pulmonary neutrophilic inflammation, remain poorly understood. This study investigates airway remodeling in acute and chronic experimental asthma models induced by house dust mite extract to elucidate inflammatory and structural changes. Two acute T2‐low models demonstrated pronounced airway inflammation characterized by goblet cell hyperplasia, collagen deposition, and significant upregulation of extracellular matrix remodeling and fibroblast activation. In contrast, the chronic Th17‐mediated model exhibited reduced ECM deposition, increased matrix metalloproteinase (MMP) activity, and a distinct molecular signature dominated by IL‐17A‐driven pathways, indicative of ECM degradation and structural instability. Furthermore, the acute models showed immune cell apoptosis as the predominant cell death mechanism. In contrast, the chronic inflammation model was marked by necroptosis localized to structural lung cells, contributing to persistent inflammation and remodeling. Our findings provide new insights into the distinct immunopathological mechanisms underlying airway remodeling and fibrosis in T2‐low and Th17‐mediated asthma phenotypes. The study emphasizes the need for advanced preclinical models and targeted therapeutic strategies to address ECM dysregulation and chronic inflammation to progress in airway remodeling treatment in asthma.