Sphingolipid metabolism is a complex system regulating important cellular processes including cell fate and inflammation. The interconnected network of sphingolipids, the many enzymes that regulate their interconversion and the compartment-specific roles all contribute to the heterogeneity of their biological actions. Besides mediating indispensable biological processes, the perturbation of sphingolipid metabolism contributes to several diseases including cancer, inflammation, neurodegenerative disorders and metabolic disorders such as diabetes and atherosclerosis.
This thesis explores the possible role of sphingolipid metabolism – particularly the involvement of the sphingolipid rheostat – in two highly prevalent lung diseases, OSA and NSCLC, with a focus on the proinflammatory and pro-survival aspects. Significant elevation of both S1P and anti-ceramide antibody levels were observed in our studies.
In the NSCLC cohort, which included patients with unresectable, advanced-stage disease, increased pre-treatment S1P levels were consistent with previous studies implicating the role of S1P in promoting tumor cell survival and progression. As reliable biomarkers are needed in lung cancer diagnosis, S1P might be a promising non-invasive diagnostic biomarker based on our results. Anti-ceramide antibody levels were also elevated in NSCLC patients, both in circulation and in bronchial samples, suggesting that anti-ceramide antibody might be produced by the tumor and its microenvironment. We hypothesize that anti-ceramide antibodies might have a neutralizing effect against pro-apoptotic signaling of ceramides. Furthermore, higher anti-ceramide antibody levels showed a tendency for prolonged OS. Our results make a basis for following investigations exploring the diagnostic and prognostic value of sphingolipids in NSCLC.
In OSA, where chronic inflammation and microvascular damage are central to disease pathology, our findings similarly demonstrated elevated S1P and anti-ceramide antibody levels, even in patients with mild disease. Anti-ceramide antibodies positively correlated with BMI, suggesting an interaction with obesity-related metabolic alterations. However, the significance of this correlation remains uncertain, as elevated antibody levels persisted after adjusting for BMI. Based on our results, altered sphingolipid metabolism might possibly mediate pathological processes in OSA.
