Abstract Rationale Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial and heterogeneous condition characterized by progressive and irreversible airflow limitation. The disease is primarily caused by an excessive inflammatory response in the lung to inhaled irritants and pathogens. Its manifestations include chronic bronchitis and emphysema, which often overlap and occur with different severity grade, with episodic exacerbations caused by bacterial and viral respiratory infections. Despite being the third leading cause of death worldwide and extensive research efforts into its complex pathophysiology, current pharmacological treatments are ineffective in halting disease progression. A major barrier to the development of novel therapeutic strategies is the lack of animal models that accurately recapitulate the complex features of human COPD. In this context, the present study aimed to characterize a murine model, induced by a combination of three different noxious stimuli, that effectively mimics key aspects of the disease in a relative short induction time. Methods Porcine Pancreatic Elastase (PPE), lipopolysaccharide (LPS) of Pseudomonas aeruginosa and polyinosinic:polycytidylic acid (Poly I:C) were administrated to female BALB/c mice to induce mild emphysema, mucus hypersecretion, and simulate both bacterial and viral infection. Furthermore, the effect of systemic corticosteroids was evaluated by treating mice with Dexamethasone, when model major features have already emerged, but not completely evolved. A deep characterization of the model was performed at molecular, histological, and imaging level at different time points (2, 3 and 4 weeks after the experiment beginning). At the last time point functional parameters and inflammatory infiltrate were also assessed. Results The stimuli combination caused a strong and progressive up-regulation of the two occlusive mucins (MUC5AC and MUC5B) and a mixed inflammatory infiltrate in the lung. Histological analysis displayed increased bronchial epithelial thickness and parenchymal destruction over time. Accordingly, lung function decline, loss of elastic recoil and air trapping were revealed by flexiVent and micro-Computed Tomography (micro-CT). Transcriptomic and proteomic analysis highlighted that these pathological changes were accompanied by deregulation of distinctive pathways. Those associated with extracellular matrix (ECM) remodeling and necroptosis were upregulated, while vasculature development and epithelium morphogenesis resulted downregulated. Dexamethasone partially restored inflammatory related processes without improving altered mucus production and emphysema, as observed in COPD patients. Conclusions Overall, the results corroborated the translational relevance of this murine model, since it successfully reproduced the main hallmark of COPD, thereby providing a useful platform for investigating disease mechanisms and for evaluating the efficacy of new drug candidates to treat COPD. This abstract is funded by: None
Gualandri et al. (Fri,) studied this question.
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