A NOVEL PRECLINICAL MOUSE MODEL TO INVESTIGATE MIXED INFLAMMATORY PHENOTYPES AND MUCUS HYPERSECRETION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Chronic obstructive pulmonary disease (COPD) is a progressive, irreversible lung condition characterized by persistent airflow obstruction, often triggered by an excessive and uncontrolled inflammatory response to harmful agents. In the past few years, the incidence of COPD has notably increased in both sexes, largely due to environmental exposures, firstly cigarettes smoke, and genetic predisposition. Beyond disease onset, the progression and clinical burden of COPD are shaped by comorbidities and recurrent exacerbations, which significantly impair lung function and clinical outcomes. COPD is associated with high risk of morbidity and mortality due to its heterogeneous progression and limited therapeutic options. Although recent advancements, first of all the development of novel biological therapies targeting the type 2 inflammatory phenotype, have been made, significant unmet medical need still persist. This mainly concerns patients with a type 1 or mixed inflammatory phenotype, which are often resistant to standard inhaled corticosteroids (ICS). To improve patient healthcare and accelerated drug discovery process, robust animal models are still essential to elucidate the underlying molecular mechanisms and accelerate the identification of new therapeutic targets. However, progress remains limited due to the absence of novel preclinical models that fully recapitulate the complex COPD phenotype and that are predictive and translationally relevant. The main goal of this Ph.D. work was to develop, characterize and optimize a new In Vivo preclinical model to advance our limited understanding of the pathogenetic mechanisms underlying COPD. The proposed model recapitulates some key hallmark of the disease, including a mixed inflammatory phenotype, mucus hyperproduction and viral infection, which may increase the risk of exacerbation. One key objective was to evaluate the translational value of this new murine model in reflecting human disease, particularly in terms of involved molecular pathways, impaired pulmonary function and current therapeutic limitations. To achieve these goals, histological analysis, biomolecular techniques, inflammatory cells and biomarkers evaluation and pulmonary function test were performed. Obtained results showed that the pathological condition induced by the combination of the antigenic cocktail AAH and the viral stimulus Poly I:C closely mimic the mixed inflammatory phenotype and mucus hyperproduction observed in COPD. Interestingly, this combination of stimuli showed a trend toward reduced pulmonary function in mice. Proteomic analyses revealed the involvement of genes enriched in pathways that may serve as novel COPD biomarkers and therapeutic targets, as well as the activation of mechanisms that counteract viral insults. The model was partially responsive to a corticosteroid treatment commonly used in the clinical practice. This Ph.D. work provides a solid starting point for studying the dysregulated processes and the key features that drive COPD, offering an innovative preclinical model for testing new potential therapeutic molecules, identifying targeted treatments to address an unmet medical need.