Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.

Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1ß and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.

Functional and proteomic analysis of serum and cerebrospinal fluid derived from patients with traumatic brain injury: a pilot study.

BACKGROUND: An enhanced fracture healing response has been reported in patients with traumatic brain injury (TBI). This has been attributed to circulating humoral factors that are thought to be proteins produced and released by the injured brain. However, these factors remain unknown. The aim of this study was to identify osteogenic factors in serum and cerebrospinal fluid (CSF) from TBI patients. This was carried out using in vitro proliferation assays with the human foetal osteoblastic 1.19 cell line (hFOB) combined with a novel proteomic approach. METHODS: Serum was collected from brain-injured (n = 12) and non-brain-injured (n = 9) patients with a comorbid femur shaft fracture. Similarly, CSF was obtained from TBI (n = 7) and non-TBI (n = 9) patients. The osteoinductive potential of these samples was determined by measuring the in vitro proliferation rate of hFOB cells. Highly osteogenic serum and CSF samples of TBI patients were chosen for protein analysis and were compared to those of non-brain-injured patients. A new hFOB cell-based method was used to enrich the proteins in these samples, which had a functional affinity for these osteoprogenitor cells. These enriched protein fractions were mapped using two-dimensional gel electrophoresis and protein imaging methods displaying serum and CSF proteins of brain-injured and control subjects that had an affinity for human osteoprogenitor cells. RESULTS: Serum and CSF derived from brain-injured patients demonstrated a greater osteoinductive potential (P < 0.05) than their non-brain-injured counterparts. Clear-cut differences in the pattern of proteins in two-dimensional gels were detected between TBI and control patients. Fourteen proteins were exclusively present in the serum of TBI patients, while other proteins were either up- or downregulated in samples collected from TBI patients (P < 0.05). CONCLUSION: Osteoinductive factors are present in the serum and CSF of brain-injured patients. These may include one or more of those proteins identified as having an affinity for osteoprogenitor cells that are either exclusively present or up- or downregulated in the serum and CSF of brain-injured patients.

[Oxidative stress in victims with heavy combined cranium-facial trauma].

For acute posttraumatic period of heavy combined cranium-facial trauma (CFT) considerable activation of peroxide lipids oxidation in the liquor is typical beginning from the 1st day of posttraumatic period on the background of speedy and drastic depletion of fermentative and low-molecular antioxidant liquor system (in spite of introduction of antioxidants particularly a-tocopherol acetate). Non-adequate functioning of the system of antioxidant defense on the background of free radical activity splash can be considered as breakdown of the process of adaptive reaction forming. It leads to weighting the course of posttraumatic period of heavy combined cranium-facial trauma and its outcome as a whole.

[Microbiological investigation of blood, urine, cerebrospinal fluid, and soft tissue material from corpses with purulent and inflammatory foci].

A microbiological investigation conducted by the author allowed her to formulate differential-diagnostic signs of the time of death in persons who die of pyoinflammatory complications of polytrauma: up to 24 hours ago or more than 24 hours. Differences in the count of the pathogens depending on the time of death are demonstrated.

Granulocyte colony-stimulating factor inhibits neutrophil apoptosis at the local site after severe head and thoracic injury.

BACKGROUND: Tissue injury from mechanical trauma often leads to secondary organ failure. Local accumulation of neutrophils and excessive release of toxic metabolites through inhibition of neutrophil apoptosis may be responsible for capillary leakage and irreversible damage of resident cells of injured tissues. METHODS: The purpose of this study was to examine the presence of apoptosis-inhibiting factors at the local site of tissue injury. Cerebrospinal fluid (CSF) from patients with severe head injury (n = 10; Abbreviated Injury Scale score, 4.5 +/- 0.2 points) and bronchoalveolar lavage fluid (BALF) from patients with serious chest trauma (n = 10; Abbreviated Injury Scale score, 4.1 +/- 0.1 points) were collected on days 1 and 3 after injury and compared with CSF (n = 5) and BALF (n = 16) obtained from patients undergoing elective orthopedic surgery. Neutrophils from healthy humans were incubated with 10% of CSF or BALF for 16 hours. Neutrophil apoptosis was determined by flow cytometric analysis of propidium iodide nuclear staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and May-Grunwald-Giemsa staining. Levels of granulocyte colony-stimulating factor (G-CSF) in CSF and BALF were measured with enzyme-linked immunosorbent assay. RESULTS: CSF and BALF from injured patients significantly inhibited spontaneous neutrophil apoptosis of healthy humans compared with control samples, whereas respiratory burst activity was enhanced (p < 0.05). Moreover, CSF and BALF from injured patients contained increased (p < 0.05) amounts of G-CSF. Neutralization of G-CSF in CSF and BALF from injured patients using monoclonal anti-G-CSF antibody markedly (p < 0.05) reduced the apoptosis-inhibiting effect of those body fluids and decreased the respiratory burst. CONCLUSION: In patients with severe head or chest injury, G-CSF acts locally as a strong inhibitor of spontaneous neutrophil apoptosis, which may cause an increased destructive potential of neutrophils present in injured tissues.