A severe traumatic brain injury (TBI) holds deleterious consequences for the afflicted, its
next-of-kin and society. Still today, prognosis is semi-desolate. One explanation for this
might be pathophysiological processes ensuing the primary trauma that are but indirectly
targeted for treatment. Among such processes, blood-brain barrier (BBB) disruption and
neuroinflammation constitute two astrocyte-dependent mechanisms that interplay in the
aftermath of a severe TBI. The overall aim of this thesis was to characterize both BBB
disruption and neuroinflammation translationally.
In paper I, n = 17 patients with severe TBI were included in a prospective observational
longitudinal study. Here, the protein biomarkers S100B and neuron-specific enolase (NSE)
were sampled with high temporal resolution from both cerebrospinal fluid (CSF) and blood.
We found that BBB disruption occurred among numerous patients and remained throughout
the first week following injury. Interestingly, BBB disruption also affected clearance from
brain to blood of S100B, but not NSE. This indicates that biomarkers are cleared differently
from the injured CNS. We elaborated on this by utilizing a larger cohort size (n = 190
patients), which enabled outcome prediction modelling, in paper II. In this prospective,
observational, cross-sectional study, we found that BBB disruption comprised a novel,
independent outcome predictor that strongly related to levels of neuroinflammatory proteins
in CSF and inflammatory processes within the injured brain. Among pathways assessed,
particularly the complement system entailed proteins of future interest. We next assessed the
relationship between in situ neuroinflammatory protein expression, BBB disruption, and
brain edema in paper III. By utilizing a rodent model of severe TBI, we found that the
cytotoxic edema region was associated with an innate neuroinflammatory response, and
astrocytic aquaporin-4 retraction from the BBB interface. In fact, the astrocyte itself is an
important neuroinflammatory cell, which we showed in paper IV, where we constructed a
disease-modelling system of stem cell-derived astrocytes that we exposed to
neuroinflammatory substances. Following neuroinflammatory stimulus, astrocytes exhibited
an important increase in canonical stress-response pathways. Importantly, following
stimulation with clinically relevant neuroinflammatory substances seen in human TBI from
paper II, they also acquired a neurotoxic potential, of plausible importance for local cell
survival following a severe TBI.
Taken together, BBB disruption and neuroinflammation ensue a severe TBI.
Neuroinflammation, particularly mediated by the complement system, stands out as a future
therapeutic target in order to mitigate exacerbated BBB disruption. Locally in the lesion
vicinity, additional neuroinflammatory mechanisms are in part mediated by astrocytes, where
these cells seem to have an important role in local cell survival. Onwards, our findings
suggest that future efforts should be directed at evaluating if neuroinflammatory modulation
of complement inhibition yields improved outcome, while elaborating on the promising
experimental data of astrocyte-mediated effects in the lesion vicinity