Plasma-Type Gelsolin Is Decreased in Human Blood and Cerebrospinal Fluid After Subarachnoid Hemorrhage

Abstract

Background Subarachnoid hemorrhage (SAH) pathophysiology involves neurovascular proteolysis and inflammation. How these two phenomena are related remains unclear. We hypothesize that matrix metalloproteinases (MMPs) mediate the depletion of anti-inflammatory plasma-type-gelsolin (pGSN). Methods We enrolled 42 consecutive SAH subjects and sampled CSF and blood on post-SAH days 2–3, 4–5, 6–7, and 10–14. Controls subjects were 20 consecutive non-SAH hydrocephalus patients with lumbar-drains. LISA, western blotting and zymography were used to quantify pGSN and MMP-9. Results In CSF, pGSN was lower in SAH compared with control subjects on post-SAH days 2–3 (p =0.0007), 4–5 (p=0.041), and 10–14 (p=0.007). In blood, pGSN decreased over time (p=0.001), and was lower in SAH compared to control subjects on post-SAH days 4–5 (p=0.037), 6–7 (p=0.006), and 10–14 (p=0.006). Western blots demonstrated that SAH CSF had novel bands at 52 and 46 kD, representing cleaved pGSN fragments. Gelatin zymography showed that CSF MMP-9 was elevated in SAH compared with controls. Higher CSF MMP-9 correlated with lower CSF pGSN on post-SAH day 7 (r= −0.38; p= 0.05). Conclusion SAH is associated with decreased CSF and blood pGSN and elevated CSF MMP-9. Novel cleaved pGSN fragments are present in CSF of SAH subjects, consistent with pGSN cleavage by MMPs. Since pGSN is known to inhibit inflammatory mediators, these findings suggest that MMPs may reduce pGSN and exacerbate inflammation after SAH. Further studies are warranted to investigate the mechanisms underlying MMP-pGSN signaling in SAH.

Plasma-type gelsolin in subarachnoid hemorrhage: novel biomarker today, therapeutic target tomorrow?

“…Previous research has shown pGSN to be present in the CSF compartment in SAH and that MMPs may mediate the depletion of pGSN [9,12]. Taken together, these studies suggest that, in the case of SAH, pGSN may be more than just a non-specific marker.…”

Soluble and Catalytically Active Endothelin Converting Enzyme-1 is Present in Cerebrospinal Fluid of Subarachnoid Hemorrhage Patients

“…Detailed descriptions of biorepository methods have been previously published (3,4). SAH subjects were included if they present within 96 h of spontaneous aneurysmal or pre-pontine SAH and had hydrocephalus requiring external ventricular drain (EVD) placement.…”

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

“…Subarachnoid hemorrhage significantly upregulates both the expression and activity of matrix metalloproteinase-9 (MMP-9) in blood and CSF. 59–61 Several different experimental models suggest that MMP-9 activity mediates blood-brain barrier breakdown and subsequent vasogenic edema following aSAH. Genetic deletion of MMP-9 both protects the integrity of the blood-brain barrier 62 and reduces edema formation 63 in mouse models of aSAH.…”