Aneurysmal subarachnoid hemorrhage (aSAH) typically results from a ruptured aneurysm and is a clinical syndrome with 45% mortality and disability with morbidity of approximately 6–16 per 100000 individuals every year all around the world, which occured at youny age and accounted for 5–7% of the total incidence of stroke[1, 2]. A major prognostic determinant is the characteristics of the initial hemorrhage, which causes early brain injury (EBI) and early cerebral vasospasms, and may be associated with delayed cerebral ischaemia (DCI). Recently, researchers have increasingly found that EBI after SAH may be the leading factor contributing to an unfavourable outcome of SAH patients[4, 5]. Therefore, the importance of pathophysiologic mechanisms in the very early phase after aSAH with changes including microvascular filling defects, breakdown of ionic homeostasis, inflammation, and microarterial narrowing[6–8]. Moreover, a reliable, early, economic and non-invasive approach is urgently in need to provide screening to patients in order to improve the prognosis of patients with aSAH.
Accumulating studies revealed small extracellular vesicles (sEVs), which are lipid membrane vesicles, could cross blood-brain barrier(BBB) and actually specialized in long distance intercellular communications facilitating transfer of proteins, lipids, and nucleic acid for subsequent protein expression in target cells[9, 10]. sEVs also released by brain cells are able to cross the BBB and can be detected in blood circulating[11–13]. Similarly, endothelial and peripheral cells secrete sEVs into the circulation. sEVs can be enriched from peripheral blood samples and used for detection of various proteins, lipids, and nucleic acids. Together, these circulating sEVs could potentially be ideal biomarkers to reflect the pathological progress of aSAH. Several clinical studies have examined circulating sEVs contents, including functional proteins and various nucleic acid species as biomarkers for cerebral ischemia[15–19].
There is substantial evidence that the inflammatory response occured early after SAH and contributed to the progression of SAH-induced EBI[4, 8, 20]. Potential biomarkers that have been studied of inflammatory cytokines such as interleukin-1α(IL-1α), IL-1β, IL-6, IL-8,IL-18, and tumor necrosis factor-alpha[21–23]. IL-6 is a proinflammatory cytokine in response to acute brain injury and other diseases[17, 24, 25]. Several studies have demonstrated elevated IL-6 levels may induce neuroinflammation and may be closely associated with the prognosis of aSAH patients[23, 26, 27].
Therefore, we hypothesize that aSAH leads to changes in the expression of IL-6 in sEVs in the brain and that these NDSEVs are secreted into circulating where they may serve as biomarkers for aSAH.In the present study, we extracted NDSEVs from the plasma of aSAH patients and healthy controls to determine the expression of IL-6 levels in NDSEVs and, ultimately, we detected increased IL-6 levels in NDSEVs of aSAH patients, which evaluated possible associations between the markers of early inflammatory response and disease progression.