To Assess the Role of Sphingosine-1-phosphate in the Pathobiology of Pneumonia: Generate a New Strategy for Treatment of Severe Community-acquired Pneumonia

Lower respiratory tract infections are the most frequent infectious cause of death worldwide[1] and impose a considerable burden on healthcare resources. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and has both extracellular and intracellular effects in mammalian cells[2-5]. S1P is involved in many physiological processes including immune responses and endothelial barrier integrity[6-9]. In the context of endothelial barrier integrity, S1P plays a crucial role in protecting the lungs from the pulmonary leak and lung injury. [10-13] Previous research suggests that, at low concentrations, S1P signaling through S1PR1 is crucial for enhancing endothelial barrier function. [13,14] The S1P induces actin polymerization and results in the spreading of endothelial cells, which fill the intercellular gaps. Also, the S1P signaling can stabilize the endothelial cell-cell junctions, such as adherens junction and tight junction. [15-17] Both actin-dependent outward spreading of endothelial cells and cell junction stabilization enhance the endothelial barrier function. However, S1P at higher concentration (> 5 µM) causes endothelial barrier disruption through binding of S1PR2[13]. Thus, exact maintenance of physiologic S1P concentrations and homeostasis of S1PRs and S1P synthesis and degradation seem to be crucial for the preservation of lung endothelial barrier integrity, particularly in inflammatory lung diseases.

Because of the involvement in lung injury and endothelial barrier function, S1P may be a potential biomarker of pneumonia. Moreover, a recent study proposed that targeting the S1P/S1P receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumonia for the prevention of acute lung injury [18]. Recently, our pilot study suggests that the patients with CAP (N= 137) have significantly higher plasma S1P levels than controls (N= 78). Further, the S1P levels, but not CRP, were found to be inversely correlated with PSI score, CURB-65 score and hospital length of stay (LOS) in patients with CAP. Our initial findings suggest that plasma S1P is a potential biomarker for predicting prognosis in CAP.

Although corticosteroids adjuvant therapy for CAP is still controversial, a recent meta-analysis study showed that corticosteroids adjuvant therapy in patients with the severe CAP could reduce the rate of in-hospital mortality and reduce the length of hospital stay[19]. Recently, the long-standing dogma of cytokine repression by the glucocorticoid was challenged. Vettorazzi et al. proposed a new mechanism of glucocorticoid action. They suggested that increased circulating sphingosine 1-phosphate levels resulting from the induction of sphingosine kinase 1 (SphK1) by glucocorticoids were essential for the inhibition of pulmonary inflammation[20]. Interestingly, our observational study also showed significantly elevated S1P levels in patients who were treated with methylprednisolone during hospitalization.

Several studies have suggested that S1P can enhance pulmonary endothelial cell barrier function, suggesting that higher S1P levels could be potentially beneficial. Hence, the patients, who are unable to produce sufficient S1P, might have a poor prognosis. However, in most of the studies, CAP was not considered as a disease model, and those results were based on cell lines and mouse models. Therefore, further clinical studies focusing on the role of S1P in the pathophysiology of pneumonia is needed.