Comprehensive characterization of a novel preclinical model mimicking the complex phenotype of Chronic Obstructive Pulmonary Disease (COPD)

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 inflammation response in the lung to inhaled irritants and pathogens. Its manifestations include chronic bronchitis and emphysema, which often overlap and occur with different grade of severity, and 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 develop a murine model that effectively mimics key aspects of the disease in a relative short time of induction by employing a combination of three noxious stimuli: Porcine Pancreatic Elastase (PPE) to induce mild emphysematous lesions, Lipopolysaccharide (LPS) of Pseudomonas aeruginosa to simulate bacterial infection, and Polyinosinic:polycytidylic acid (Poly I:C) to mimic viral infection. This model successfully reproduced the main hallmark of COPD, including inflammation, mucus overproduction and tissue damage in murine lungs. The deep characterization of the model at molecular, histological, and functional level at different time points enabled to understand that these pathological changes were accompanied by deregulation of distinctive pathways by transcriptomic and proteomic analysis, alteration of inflammatory protein levels, histological architecture as well as lung mechanical and densitometric parameters. Furthermore, the effect of systemic corticosteroids was also evaluated by treating mice with dexamethasone, when model major features have already emerged, but not completely evolved. Dexamethasone sensitive and resistant mechanisms in the animal model were elucidated. Finally, the comparative analysis with published data ensured the translational relevance of the induced features in the murine model with clinical COPD phenotypes, thereby providing a useful platform for investigating disease mechanisms and for evaluating the efficacy and safety of novel drug candidates for the treatment of COPD.