Granato, Elisabetta (2024) Role of Sphingolipids in the development of chronic lung diseases. [Tesi di dottorato]

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Abstract

This thesis project highlighted the important role of sphingolipids in the development of chronic respiratory diseases, such as asthma and COPD; particularly we demonstrated that S1P is an inducer of an important asthma feature, such as EMT, through the regulation of TGF‐β. Furthermore, we found an important connection between sphingolipids and sexual hormones, suggesting that the hormone's role in the development of chronic lung disease and sex-related symptoms, is due to the interaction with sphingolipids. Indeed, our data support the hypothesis of sex-related differences in the lung, which contribute to differential susceptibility to the development of asthma and COPD. Another important goal was to synthesize new drugs that could optimize the pharmacological activity of drugs already used for the treatment of lung diseases such as β2-agonists and corticosteroids. In this context, we demonstrated the efficacy of the combination of beta-agonist formoterol with Montelukast, an anti-leukotriene used for asthma therapy, in overcoming the β2 receptor desensitization and preserving the rescue therapy as well as reducing AHR and lung inflammation. Another drug combination that resulted positively in the management of asthma features, was, Prednisone, a common anti-inflammatory drug, combined with TBZ, an H2S slow-releasing molecule; this hybrid provides a suitable approach to managing asthma features with a particular impact on airway remodeling.

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