Divergent Mechanisms of Tissue Remodeling In Acute and Chronic Models of Allergic Airway Inflammation

Inadequately controlled chronic airway inflammation may result in a series of irreversible changes within lung tissue, referred to as lung remodeling. The increased activation of airway fibroblasts and their differentiation towards myofibroblasts leads to the deposition of extracellular matrix (ECM) components, including collagens. The disrupted balance between the activity and concentration of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) secreted by structural lung cells and infiltrating immune cells may lead to excessive ECM remodeling. Here, we aimed to utilize HDM-induced experimental acute (mixed and neutrophilic) and chronic (neutrophilic) experimental asthma models to assess differences in lower airway remodeling. First, we confirmed increased total collagen deposition within the lung in all analyzed models. Additionally, we found an elevated frequency of IFN?-producing T cells in acute neutrophilic inflammation, while an elevated frequency of IL-4 and IL-10-producing T cells was observed in mixed airway inflammation. Transcriptomic analysis revealed Th2- and Th17- -related signaling pathways, while specifically in the chronic model, we noted Th17-driven fibrosis. Moreover, transcriptomic profiling showed the dysregulation in genes associated with ECM morphology, collagens, MMPs, and TIMPs. Targeted protein analysis confirmed the increased deposition of Collagen I, III, IV, and VI. Finally, multiplexing analysis of bronchoalveolar lavage indicated an increase in MMP-2 and TIMP-4 levels among all investigated models, whereas MMP-8 and MMP-9 appeared to be increased explicitly in chronic inflammation. In summary, we confirmed that various inflammatory profiles in experimental asthma models may differentially influence the development of airway remodeling changes. Overall design: Female C57BL/6cmdb mice were divided into five groups. Mice were sacrificed after 2 weeks (models with 10 µg, 100 µg of HDM extract and control) and 12 weeks (models with 100 µg of HDM extract and control). Biological material was collected and biobanked for further analysis.