In this study, we found that subjects with OSA have significantly elevated plasma APRIL, MCP-1 and L-selectin levels compared with controls. Plasma APRIL concentrations were the lowest in mild OSA subjects and increased as the AHI increased, with the highest concentrations in the severe OSA group. Plasma APRIL levels were significantly correlated with the AHI and the “Lowest SaO2”, and by multiple regression analyses, we found APRIL were positively and independently associated with the OSA and the AHI, respectively. Meanwhile, plasma APRIL showed higher discriminatory accuracy than plasma MCP-1 and L-selectin in predicting OSA.
Sleep deprivation, sympathetic activation, and CIH was the major pathophysiologic character of OSA, which lead to the release of proinflammatory mediators and the directional migration of leucocytes. These pathophysiological changes can stimulate the expression of acute-phase proteins and inflammatory mediators [2, 5]. Meanwhile, immune cells dominate early atherosclerotic lesions, their effector molecules accelerate inflammation and NF-KB activity, which can elicit atherosclerotic lesions rupture and trigger the acute onset of arterial thrombosis [30, 31]. Several studies have shown that treating OSA with continuous positive airway pressure improves inflammation and reduces of NF-KB signaling [20, 32]. Even in patients with OSA who were free of overt cardiovascular disease, the physiological perturbations of inflammation and NF-KB-dependent inflammatory pathways activation often caused blood pressure and heart rate elevations, ventricular failure, myocardial infarction, and stroke [4, 33]. Given its association with cardiovascular disease, it was extremely essential to advance the research agenda to explore validated tools for diagnosing OSA in the early stage.
The AASM clinical practice guidelines suggest that OSA is diagnosed based on clinical measures, including the subjective assessment of somnolence and the overnight multi-channel PSG . The former is limited by low specificity and accuracy for diagnosis of OSA, the latter is expensive, labor-intensive, time-consuming tests and impractical for the clinical evaluation of large at-risk populations . Therefore, new technologies such as circulating biomarkers could provide important information on clinical significance for diagnosing OSA.
By human Magnetic Luminex assay, we evaluated plasma APRIL, MCP-1, and L-selectin levels in subjects with confirmed OSA and controls. Intriguingly, we found that plasma APRIL, MCP-1, and L-selectin levels were significantly higher in the OSA group compared with the control group. In addition, plasma APRIL levels were statistically higher in subjects with severe OSA than subjects with mild OSA. APRIL(also named TNFSF13), a member of the tumor necrosis factor family, which is secreted as a soluble factor at low levels in immunological tissues especially by antigen-presenting cells, inactive B cells, T cells, monocytes, neutrophils, macrophages, and dendritic cells, as well as by epithelial cells, osteoclasts, and megakaryocytes [34–36]. Increased levels of APRIL have been found in several autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and immunodeficiency [11–14]. Several studies have indicated that the relationship of APRIL and NF-KB signaling pathway activation is one of a complex interactive, APRIL could induce inflammatory activation by the activation of NF-KB signaling pathway [15, 16], and conversely, NF-KB-dependent pathways can influence APRIL secretion [17, 18]. A large body of evidence, including experimental and clinical studies, have demonstrated that the activation of NF-KB–dependent inflammatory pathways by intermittent hypoxia and reoxygenation in OSA may be an important molecular mechanism of cardiovascular complication [4, 19, 20]. Moreover, both RNA and protein expression of APRIL have been shown in human plaque lymphocytes and macrophages and plasma [37, 38]. Recently, Bernelot Moens et al found that APRIL transgenic mice do show potential plaque stabilizing features in advanced atherosclerotic lesions . However, to the best of our knowledge, no previous studies have investigated the relationship between the circulating APRIL and the presence of OSA. The present study showed that a progressive increase in the concentrations of APRIL with the severity of OSA, increase plasma APRIL levels were significantly associated with the occurrence of OSA and its severity.
MCP-1 is one of the best-studied CC chemokines that is expressed by inflammatory cells and stromal cells, and its chemotactic activity could be upregulated after proinflammatory stimuli [40, 41]. Evidence from animal models and in vitro experiments suggested that IH induced the synthesis and expression of MCP-1 via the activation of NF-KB signaling pathway [21, 42]. Furthermore, early studies suggested that OSA-induced hypoxia would increase circulating MCP-1 levels and effective therapy for OSA could reduce the expression of MCP-1 [43, 44]. Our results suggested that the plasma MCP-1 level was significantly higher in subjects with OSA compared with subjects without OSA, but there were no statistical differences in MCP-1 levels among the mild OSA, moderate OSA, and severe OSA.
L-selectin is a cell membrane-surface receptor on leukocytes, which mediated the rolling and tethering of leukocytes into the injured tissues independently of other adhesion molecules . Early studies found that the monocyte/leukocyte induced effects on expression of the L-selectin through the NF-KB signaling pathway . Meanwhile, some evidence demonstrated that circulating L-selectin levels were significant and independent indicators of accentuated atherogenesis in patients with OSA [24, 45]. However, some studies showing the correlation between circulating L-selectin and OSA were not detected, probably due to the defining criteria of the OSA were inconsistent [46, 47]. In the present study, we found that the circulating L-selectin levels were significantly increased in the OSA group, and it was independently associated with the occurrence of the OSA and its severity. Of note, no significant differences in L-selectin levels were observed among the mild OSA, moderate OSA, and severe OSA.
And intriguingly, we also found that plasma APRIL levels were significantly correlated with plasma MCP-1 and L-selectin levels. Of note, in terms of AUC, the discriminatory accuracy of plasma APRIL significantly exceeded those of plasma MCP-1and L-selectin. These interesting findings implied that plasma APRIL levels might be related to inflammation and NF-KB–dependent inflammatory pathways activation induced by OSA.
Care was taken to avoid bias in this study, the Luminex experiment was performed according to the manufacturer’s instructions by a trained experimenter who was unaware of patients' clinical data. Moreover, in the statistical analysis, adjustments were made for the confounding effects of risk factors for plasma APRIL levels and OSA/AHI. However, our study had several certain limitations. First, we included only newly diagnosed, and untreated OSA. Second, our results didn't elucidate the specific mechanisms of APRIL in OSA.