Conventional surfactant proteins (A, B, C, and D) are important players of the innate immunity in the central nervous system and serve as effective regulators of cerebrospinal fluid rheology, probably being involved in clearance of detrimental metabolites like beta-amyloid and phospho-tau. Recently, a novel surfactant protein, SP-G, was described in kidneys and peripheral endocrine and exocrine glands. So far, its presence and possible functions in the central nervous system are unknown. Therefore, our study aimed to elucidate the presence of SP-G in the brain and its concentration in normal and pathologic samples of cerebrospinal fluid in order to gain first insight into its regulation and possible functions. A total of 121 samples of human cerebrospinal fluid (30 controls, 60 hydrocephalus patients, 7 central nervous system infections, and 24 brain hemorrhage patients) and 21 rat brains were included in our study. CSF samples were quantified using a commercially available ELISA system. Results were analyzed statistically using SPSS 22, performing Spearman Rho correlation and ANOVA with Dunnett's post hoc analysis. Rat brains were investigated via immunofluorescence to determine SP-G presence and colocalization with common markers like aquaporin-4, glial fibrillary acidic protein, platelet endothelial adhesion molecule 1, and neuronal nuclear antigen. SP-G occurs associated with brain vessels, comparable to other conventional SPs, and is present in a set of cortical neurons. SP-G is furthermore actively produced by ependymal and choroid plexus epithelium and secreted into the cerebrospinal fluid. Its concentrations are low in control subjects and patients suffering from aqueductal stenosis, higher in normal pressure hydrocephalus (p < 0.01), and highest in infections of the central nervous system and brain hemorrhage (p < 0.001). Interestingly, SP-G did correlate with total CSF protein in patients with CNS infections and hemorrhage, but not with cell count. Based on the changes in CSF levels of SP-G in hydrocephalus, brain hemorrhage, and CNS infections as well as its abundance at CSF flow-related anatomical structures closely associated with immunological barrier systems, importance for CSF rheology, brain waste clearance, and host defense is assumable. Thus, SP-G is a potential new CSF biomarker, possibly not only reflecting aspects of CNS innate immune responses, but also rheo-dynamically relevant changes of CSF composition, associated with CSF malabsorbtion. However, further studies are warranted to validate our findings and increase insight into the physiological importance of SP-G in the CNS.
IntroductionPulmonary Surfactant reduces surface tension in the terminal airways thus facilitating breathing and contributes to host’s innate immunity. Surfactant Proteins (SP) A, B, C and D were recently identified as inherent proteins of the CNS. Aim of the study was to investigate cerebrospinal fluid (CSF) SP levels in hydrocephalus patients compared to normal subjects.Patients and MethodsCSF SP A-D levels were quantified using commercially available ELISA kits in 126 patients (0–84 years, mean 39 years). 60 patients without CNS pathologies served as a control group. Hydrocephalus patients were separated in aqueductal stenosis (AQS, n = 24), acute hydrocephalus without aqueductal stenosis (acute HC w/o AQS, n = 16) and idiopathic normal pressure hydrocephalus (NPH, n = 20). Furthermore, six patients with pseudotumor cerebri were investigated.ResultsSP A—D are present under physiological conditions in human CSF. SP-A is elevated in diseases accompanied by ventricular enlargement (AQS, acute HC w/o AQS) in a significant manner (0.67, 1.21 vs 0.38 ng/ml in control, p<0.001). SP-C is also elevated in hydrocephalic conditions (AQS, acute HC w/o AQS; 0.87, 1.71 vs. 0.48 ng/ml in controls, p<0.001) and in Pseudotumor cerebri (1.26 vs. 0.48 ng/ml in controls, p<0.01). SP-B and SP-D did not show significant alterations.ConclusionThe present study confirms the presence of SPs in human CSF. There are significant changes of SP-A and SP-C levels in diseases affecting brain water circulation and elevation of intracranial pressure. Cause of the alterations, underlying regulatory mechanisms, as well as diagnostic and therapeutic consequences of cerebral SP’s requires further thorough investigations.
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Surfactant proteins (SPs) are a multifunctional group of proteins, responsible for the regulation of rheological properties of body fluids, host defense, and cellular waste clearance. Their concentrations are changed in cerebrospinal fluid (CSF) of patients suffering from communicating hydrocephalus. Hydrocephalic conditions are accompanied by altered CSF flow dynamics; however, the association of CSF-SP concentrations and CSF flow has not yet been investigated. Hence, the aim of this study was to evaluate the association between SP concentrations in the CSF and marked CSF flow phenomena at different anatomical landmarks of CSF spaces. Sixty-one individuals (15 healthy subjects and 46 hydrocephalus patients) were included in this study. CSF specimens were analyzed for SP-A, SP-B, SP-C, and SP-D concentrations by the use of enzyme-linked immunosorbent assays (ELISA). CSF flow was evaluated in axial T2_turbo inversion recovery magnitude (TIRM)-weighted and sagittal T2-weighted magnetic resonance imaging sections using a 4-grade scale (1-no flow, 2-subtle flow, 3-moderate flow, and 4-strong flow). CSF-SP concentrations (mean ± standard deviation) of the overall collective were as follows: SP-A = 0.73 ± 0.58 ng/ml, SP-B = 0.17 ± 0.93 ng/ml, SP-C = 0.95 ± 0.75 ng/ml, and SP-D = 7.43 ± 5.17 ng/ml. The difference between healthy controls and hydrocephalic patients regarding CSF concentrations of SP-A (0.34 ± 0.22 vs. 0.81 ± 0.59 ng/ml) and SP-C (0.48 ± 0.29 vs. 1.10 ± 0.79 ng/ml) revealed to be statistically significant as calculated by means of ANOVA (p values of 0.022 and 0.007, respectively). CSF flow voids were detectable at all investigated landmarks of the CSF spaces (foramina of Monro, third ventricle, mesencephalic aqueduct, prepontine cistern, fourth ventricle, cisterna magna, and craniocervical junction). CSF flow voids, reported as mean ± standard deviation, revealed to be significantly increased in hydrocephalic patients compared to controls as calculated by means of ANOVA (respective p values are given in brackets following values of descriptive statistics) at the following sites: foramina of Monro (1.60 ± 0.91 vs. 2.37 ± 0.99, p = 0.01), fourth ventricle (1.67 ± 0.98 vs. 2.52 ± 1.05, p = 0.007), and the cisterna magna (1.93 ± 1.10 vs. 2.72 ± 1.13, p = 0.022). Spearman's rank order calculation identified significant correlations for CSF flow voids at the foramina of Monro and the third ventricle with SP-A (r = 0.429, p = 0.001 and r = 0.464, p < 0.001) and CSF flow void at the mesencephalic duct with SP-D (r = - 0.371, p = 0.039). Furthermore, SP-C showed a moderate inverse correlation with age (r = - 0.302, p = 0.022). The present study confirmed statistically significant differences in SP-CSF concentrations between healthy controls and hydrocephalic patients. Additionally, significant correlations between SP concentrations in CSF with increased CSF flow were identified. These findings underline the role of SPs as regulators of CSF rheology.
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