The Acrolein - Lipopolysaccharide Mouse Model for Frequent Exacerbations in COPD.

Abstract

Chronic obstructive pulmonary disease (COPD) is a severe progressive lung disease, often caused by prolonged exposure to cigarette smoke and environmental factors. Pre-clinical COPD research predominately relies on chronic smoke or elastase animal models, each with their own advantages and limitations, such as limited pathophysiological insights or long treatment times. Here we describe a novel and time efficient mouse model of COPD based on bacterial lipopolysaccharide (LPS) and the reactive aldehyde acrolein (Acro). Mice were treated once per week for four weeks with a combination of both LPS and Acro. Histological, inflammatory, and metabolomic alterations were analysed by histological quantification, multicolour flow cytometry, and nuclear magnetic resonance (NMR). Acro/LPS treatment induced moderate airspace enlargement and bronchial remodelling. These structural changes were associated with a distinct inflammatory profile marked by an increase in macrophages, and T-helper cells, as well as increased cytokines, including CXCL11, IL-17a, and TNF-α. Strong inflammation, consisting of T-helper and B-cells was detected in the perivascular and peribronchial space, and increased macrophages in the alveolar regions. Additionally, intervention with the steroid dexamethasone induced a strong reduction in T-cells and macrophages and partially ameliorated histological alterations. Furthermore, we could detect alterations in the metabolome of serum and tissue, including an increase in COPD associated metabolites like trimethylamine N-oxide, as well as a misbalance in energy related metabolites and several amino acids. In summary, we can describe a practical, representative, and time efficient mouse model of COPD, with the potential to study the immunological and pathophysiological development of the disease.