Original ArticleLevels of Interleukin-1β, Interleukin-18, and Tumor Necrosis Factor-α in Cerebrospinal Fluid of Aneurysmal Subarachnoid Hemorrhage Patients May Be Predictors of Early Brain Injury and Clinical Prognosis
Introduction
An aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular disease with complex mechanisms, high morbidity, and high mortality. Current studies have shown that early brain injury (EBI) plays an important role in the acute brain injury of subarachnoid hemorrhage (SAH) within the first 72 hours.1 Currently, brain edemas seen on computed tomography (CT) scans and transcranial Doppler ultrasonography (TCD) and Fisher grade and Hunt-Hess grading scales are commonly used to assess the severity of EBI.2 However, predictors of evaluating injuries of the central nervous system remain deficient. Recent studies have demonstrated that neuroinflammation after SAH plays an important role in the pathophysiologic events of EBI.3, 4 Several inflammatory mediators contribute to SAH-induced cerebral inflammation and have a damaging effect on cerebral tissues, which leads to neurobehavioral dysfunction, brain edema, blood-brain barrier disruption, and neuronal cell apoptosis.5, 6 In addition, brain-derived cytokines may enter the systemic circulation in the presence of post-SAH blood-brain barrier disruption to activate inflammatory cascades systemically and contribute to the development of post-SAH systemic inflammatory response syndrome and extracerebral organ system failures.7, 8 Therefore, we hypothesize that some of the increased inflammatory cytokine levels may be indicators of injury to the central nervous system after an aSAH.
Pathophysiologic mechanisms have been investigated in animal models for the past several decades, and neuroinflammation is thought to be a promising area of research for new treatments.3, 4, 9 The initial bleeding of a ruptured aneurysm will lead to increased intracranial pressure10 and decreased cerebral perfusion pressure.11 In addition, some toxic molecules12 are released into the cerebrospinal fluid (CSF) and activate a series of receptors, such as Toll-like receptors and nucleotide-binding oligomerization domain-like receptors, after SAH. They lead to the activation of the inflammasome and proinflammatory and inflammatory response. The inflammasome, which includes nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3, apoptosis-associated speck-like protein CARD domain, and pro-caspase-1, plays an important role in the inflammatory response.13, 14 Once the inflammasome is triggered, pro-caspase-1 is cleaved into active subunits (caspase-1 p20 and caspase-1 p10), which convert pro-interleukin (IL)-1β and pro-IL-18 into active forms, and they can be found in nearly all the mesenchymal cells in humans and mice.15 Interestingly, IL-1β and IL-18 are the downstream products of caspase-1 p20, and both are ligands of the IL-1 family, and have different forms of IL-1 receptor (IL-1R1 and IL-1RAcP) and IL-18 receptor (IL-18Ra and IL-18Rb).16 IL-1β is one of the products of blood monocytes, tissue macrophages, and brain microglia in response to toll-like receptor, activated complement components, other cytokines (e.g., tumor necrosis factor-α [TNF-a]), and IL-1 itself.17 Although TNF-α is considered to be a harmful proinflammatory cytokine in secondary brain injuries,18 a previous study has shown TNF-α has many roles in stroke, and the potential role of TNF-α remains unclear.19 Previous studies have proven that high mobility group box 1 is a trigger of inflammation, which upregulates the expression of IL-1β and TNF-α and results in brain injury.20 Some studies have mentioned that significantly elevated level of TNF-α in the CSF may cause an unfavorable outcome.21, 22 Therefore, this study was designed to investigate the levels of inflammatory cytokines, including IL-1β, IL-18, and TNF-α in the CSF of aSAH patients and correlate them with both the degree of EBI measured by traditional predictors and the neurologic outcome.
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Patients and Exclusion Criteria
aSAH patients and controls who were prospectively enrolled between February 2016 and March 2017 in the Department of Neurosurgery, Jinling Hospital, Nanjing, China, and diagnosed by computerized tomography and digital subtraction angiography were recruited. We excluded the patients who had previously experienced central nervous system diseases (brain tumor or stroke), acute cardiac diseases, infection, renal function disorder, or other organ dysfunctions. In addition, patients on aspirin or
Time-Dependent Profiles of Inflammatory Cytokines in aSAH Patients
The levels of IL-1β, IL-18, and TNF-α in the CSF of aSAH patients were measured by ELISA according to the time period (days 1–3, 4–6, and 7–9) after aSAH onset. The levels of IL-1β, IL-18, and TNF-α in the CSF were significantly increased in aSAH patients (Figure 1). A trend for increasing levels was observed at higher Hunt-Hess grades, World Federation of Neurological Surgeons grades, and Fisher grades within days 1–3, 4–6, and 7–9 (Figure 2), along with increased brain edema and hydrocephalus
EBIs after aSAHs
Because SAHs have a high rate of morbidity and mortality, increasing numbers of studies have focused on EBI.30, 31, 32 EBI is thought to be an important cause of an unfavorable outcome after SAH.33 Once an aneurysm ruptures, blood extravasates from a ruptured defect and spreads into the subarachnoid space, leading to a sharp elevation in intracranial pressure. The rise in intracranial pressure and subsequent fall in cerebral perfusion pressure results in a significant decrease in the cerebral
Conclusions
The levels of IL-1β, IL-18, and TNF-α in CSF were elevated in aSAH patients and were positively associated with cerebral edema and acute hydrocephalus. Our findings suggested that CSF inflammatory cytokines might be biomarkers to assess severity and predict outcomes in aSAH patients. In addition, they have a significant clinical value in the early diagnosis of brain injury, and the diagnosis rate can be increased. Finally, further mechanistic studies are needed to provide deep insight into
Acknowledgments
The authors thank the staff of the Department of Anesthesiology for sample collection.
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Cited by (0)
Conflict of interest statement: This study was supported by grants from the National Natural Science Foundation of China (81501022 and 81471183) and the Natural Science Foundation of Jiangsu Province, China (BK2014377).
Sheng-yin Lv and Qi Wu are co–first authors.