Role of sphingolipids in inflammatory respiratory diseases

Sphingolipids synthesis represents a novel metabolic pathway influencing airway function. Systemic administration of sphingosine-1-phosphate (S1P), the final product of sphingolipid metabolism, without additional adjuvant factors, induces in the mouse a disease closely mimicking the cardinal features of severe asthma such as airway hyperreactivity and pulmonary inflammation. Here, I have investigated the molecular and cellular mechanisms underlying the S1P effect on the airway during a pulmonary inflammatory disease. For this purpose, I have used different in vivo and in vitro experimental models such as asthma-like disease and a model of mild COPD. The results obtained showed a concentrated participation of TLR4, epithelium and mast cells in S1P-induced airway hyperreactivity and lung inflammation following exposure to the allergen. In addition, it has been also demonstrated that airway S1P effects are also triggered by other stimuli such as cigarette smoke. Indeed exposure of mice to cigarette smoke induces an S1P-mediated AHR in a time-dependent manner. Furthermore, I have evaluated the potential contribution of sphingolipids in coronary artery diseases (CAD) in ApoE-/- mice following pressure overload (TAC), a novel animal model of heart failure. The data obtained demonstrate the protective role of de novo sphingolipid biosynthesis in the development of coronary atherosclerosis in ApoE-/- mice post-TAC. In conclusion, this study demonstrates that S1P is a common denominator of inflammatory based diseases and proposes S1P as a potential new therapeutic target for the attenuation of symptoms of lung diseases and in vascular dysfunction associated with atherosclerosis