CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome

Abstract

Lipocalin-2 mediates neuro-inflammation and iron homeostasis in vascular injuries of the central nervous system (CNS) and is upregulated in extra-CNS systemic inflammation. We postulate that cerebrospinal fluid (CSF) and blood lipocalin-2 levels are associated with markers of inflammation and functional outcome in subarachnoid hemorrhage (SAH). We prospectively enrolled 67 SAH subjects, serially measured CSF and plasma lipocalin-2, matrix metallopeptidase 9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on post-SAH days 1-5 and assessed outcome by modified Rankin Scale (mRS) every 3 months. Unfavorable outcome is defined as mRS > 2. Twenty non-SAH patients undergoing lumbar drain trial were enrolled as controls. Lipocalin-2 was detectable in the CSF and significantly higher in SAH compared to controls (p < 0.0001). Higher CSF LCN2 throughout post-SAH days 1-5 was associated with unfavorable outcome at 3 (p = 0.0031) and 6 months (p = 0.014). Specifically, higher CSF lipocalin-2 on post-SAH days 3 (p = 0.036) and 5 (p = 0.016) were associated with unfavorable 3-month outcome. CSF lipocalin-2 levels positively correlated with CSF IL-6, TNF-α and MMP-9 levels. Higher plasma lipocalin-2 levels over time were associated with worse 6-month outcome. Additional studies are required to understand the role of lipocalin-2 in SAH and to validate CSF lipocalin-2 as a potential biomarker for SAH outcome.

Effect of stress‐induced hyperglycemia after non‐traumatic non‐aneurysmal subarachnoid hemorrhage on clinical complications and functional outcomes

“…The pathological mechanisms of EBI include oxidative stress, platelet activation, inflammation, and neuronal apoptosis 41–46 . Additionally, new studies showed that microthrombi formation, vascular injury and iron homeostasis disorder were also important mechanisms of EBI after SAH 47,48 . One animal experiment found that hyperglycemia could increase reactive oxygen species (ROS) production through activating protein kinase C after stroke, thereby exacerbating oxidative stress 49 .…”

“…[41][42][43][44][45][46] Additionally, new studies showed that microthrombi formation, vascular injury and iron homeostasis disorder were also important mechanisms of EBI after SAH. 47,48 One animal experiment found that hyperglycemia could increase reactive oxygen species (ROS) production through activating protein kinase C after stroke, thereby exacerbating oxidative stress. 49 In another study, hyperglycemia aggravated neuronal apoptosis through the activation of extrinsic caspase cascade via extracellular regulated kinase (ERK) signal pathway after experimental SAH.…”

Identification of Neutrophil-Related Factor LCN2 for Predicting Severity of Patients With Influenza A Virus and SARS-CoV-2 Infection

“…LCN2 is also upregulated in serum and liver tissue of patients with non-alcoholic fatty liver (NAFL), and serum LCN2 levels could be a novel biomarker for the diagnosis of non-alcoholic steatohepatitis (NASH), which may be participate in the transition from NAFL to NASH by mediating inflammation. Besides, LCN2 has been demonstrated as a biomarker for inflammatory bowel disease ( Thorsvik et al, 2017 ), vascular dementia ( Llorens et al, 2020 ), neuropsychiatric lupus ( Mike et al, 2019 ), and subarachnoid hemorrhage outcome ( Yu et al, 2021 ). The level of LCN2 could predict disease severity and survival in acute kidney injury ( Bennett et al, 2008 ; Kümpers et al, 2010 ).…”

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

“…One is haemolytic product-induced secondary neuroinflammatory factors, such as inflammasome-derived caspase-1 activity, which is tightly associated with blood coagulation in CSF and poor prognosis of SAH patients. 6 Elevated CSF lipocalin-2 mediates neuroinflammation and iron homeostasis and is reported to be a biomarker for unfavourable outcomes of SAH patients 7 and a potential therapeutic target for long-term neurological rehabilitation. 8 …”