Localization, Occurrence, and CSF Changes of SP-G, a New Surface Active Protein with Assumable Immunoregulatory Functions in the CNS

Abstract

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.

CSF Surfactant Protein Changes in Preterm Infants After Intraventricular Hemorrhage

“…In the present study, its concentration declines over time but does not reach normal values of neither controls nor hydrocephalus patients. This supports a role of SP-G in removal of debris and inflammatory responses in the time course of the patients, as postulated in our previous study (9).…”

“…The theory of incompetent surfactant layer function at the origin of undue periventricular shear stress as mechanism of IVH development is supported by our findings in rat brain development: SP-B and SP-D were detected in adult rats only, but not in embryonic stages (1,7,11). SP-G has been proposed to be an acute phase-associated and inflammation-mediating CNS surface-active protein (9,12). In the present study, its concentration declines over time but does not reach normal values of neither controls nor hydrocephalus patients.…”

“…Treatment of CSF circulation disturbance will lead to elution of excess CSF protein and cells, normalize intracranial pressure, and alleviate ventricular volume load. The primary CSF concentrations prior to intervention underline the CNS-borne production of SPs and make a secondary effect due to blood contamination unlikely, as previously shown in other studies (1,6,9) (Figure 3).…”

“…Furthermore, CNS borne expression of all SPs has been shown by immunohistochemical data (1,2,9,10). A disturbed or unbalanced expression of SPs might play a causative role in IVH development, and the observed elevations during acute phase situations then mirror the initial disbalance overlaid by secondary effects.…”

“…SP-A has recently found to modulate CNS immune response of astrocytes and microglial cells ( 6 – 8 ). Additionally, we have demonstrated that SP-G plays a role in CNS water hemostasis and is elevated in inflammatory and hydrocephalic conditions ( 9 ).…”