Role of sphingolipid and hydrogen sulphide pathways in inflammatory lung diseases

The importance of sphingolipids in lung pathophysiology is becoming more and more evident over years. Despite the findings that they have such numerous activities on cells, the mechanisms by which sphingolipids elicit their effects are not fully understood. Furthermore, the role of other recently-identified mediators such as gasotransmitters in pulmonary district has started to be investigated. My project aimed at clarifying the cellular/molecular pathways underlying the beneficial/detrimental effects of these mediators in lungs in animal experimental models by means of in vivo and in vitro approaches. The results obtained showed that systemic administration of S1P could induce an asthma-like condition in mice and such condition involved the cooperation and activation of different cells of the immune system, i.e. mast cells and T cells. The effects of S1P were counteracted by B cells. Conversely to the negative effects of S1P, we showed that H2S inhalation proved to be beneficial in reducing allergen-induced airway hyperreactivity via a mast cell- and fibroblast-mediated mechanisms, without affecting lung inflammation. However, in an experimental model of pulmonary hypertension, we observed that H2S acted as an antiinflammatory agent. In conclusion, a new experimental asthma-like model useful for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches has been characterised. In addition, the protective properties of H2S have been further clarified, evidencing its involvement in modulating remodeling processes in inflammatory lung diseases.