The White Blood Cell Reactivity Following Surgical Trauma and Associated Regulatory Mechanisms.
Condition: Neuroinflammation
MeSH terms: Neuroinflammatory Diseases
Study type: Observational

Summary: 
      The purpose of this study is to describe numerical and functional changes in the white blood
      cell efter surgical trauma. Further, observed immune cell changes correlate to heart rate
      variability and cognitive function will be assessed.
    

Detailed description: 
      Surgical trauma causes release of damage-associated molecular patterns (DAMPs) and other
      alarmines (e.g. HMGB-1) targeting receptors on local cells of the innate immune system, such
      as macrophages. This cellular response to trauma is followed by a rapid release of an array
      of inflammatory mediators (e.g. TNFα, IL-1B, IL-6, IL-8, IL-10) being dependent on
      intracellular activation of nuclear factor NF-kB. Until recently it was believed that the
      brain is protected from this cascade of inflammatory mediators primarily due to an intact
      blood-brain-barrier (BBB). However, there is now a growing body of evidence that long term
      impairment of brain functions is associated with trauma-induced activation of the brain
      innate immune system with subsequent impairment of higher cognitive processes and risk for
      later permanent dementia. Yet, the link between systemic inflammation and cognitive
      impairment is not fully understood.

      Recent studies have mapped periphery-to-brain-signaling after surgical trauma and the impact
      of major surgical trauma on the human brain by serial PET-imaging. In series of surgical
      patients, profound and biphasic changes in brain immune activity after surgery has been
      demonstrated after major abdominal surgery with signs of early depression followed by an
      increased immune activity at 3 months postoperatively. These biphasic changes in brain
      immunity seem to be aligned with simultaneous changes in whole blood immune reactivity to LPS
      suggesting a close link between brain and peripheral immune systems in regulation of acute
      inflammation and immune responses. Preclinical work in surgical animal models indicates
      disruption of the BBB with migration of peripheral macrophages into the brain as a pathway of
      potential importance. Evidence from an orthopedic surgery model in mice of trauma-induced
      altered hippocampal neuro-immune activity further raises the question whether peripheral
      markers of neurodegeneration (S100b, neurofilament light NFL, ptau, beta-amyloid) are
      associated with POCD.

      The immune-regulatory role of the brain via the cholinergic anti-inflammatory reflex pathway
      (mediated by the vagal nerve) has been identified as potential target for immune-modulatory
      treatment strategies in systemic inflammation. We have moreover demonstrated a distinct
      release of human carotid body inflammatory mediators at hypoxia and gene expression related
      to inflammatory mediators, suggesting a potential role of the human carotid body in
      periphery-to-brain immune-signaling. Modulation of a vagal nerve-derived inflammatory reflex
      pathway by electrical stimulation has recently been successfully applied in treatment of
      chronic inflammation among patients with rheumatoid arthritis.

      The hypothesis is that vagal nerve activity modulates systemic inflammation in patients after
      major surgery and that this modulation is associated with cognitive performance in the
      postoperative period.

      With a more comprehensive understanding of immune-to-brain signaling after surgical trauma
      and how this biphasic inflammatory response pattern is regulated by cellular and neuronal
      components, the impact of immune modulation on key processes behind surgery-induced brain
      dysfunction can be explored, and possible neural and humoral targets for relevant
      anti-inflammatory treatments established.

      In abdominal surgery patients we will map inflammatory periphery-to-brain communication by
      description of the temporal association between brain regulation of peripheral immunity
      (i.e., temporal changes in vagal nerve activity as measured by serial measurements of heart
      rate variability), repeated blood reactivity to LPS by serial ex vivo LPS challenge and
      simultaneous plasma/serum-borne CNS inflammatory and brain injury biomarkers to explore the
      impact of changes in systemic and brain immune function after surgery on long-term cognitive
      performance.
    

Intervention name(s): Cognitive testing, testing of heart rate variability and blood samples
Intervention type(s): Other
Intervention description(s): No intervention. Registration of ECG, cognitive testing and blood sampling is performed in the perioperative period and during follow up.
Observational model: Other
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients with diagnosed prostate disease who are scheduled for elective robot assisted
        prostate surgery (RALP) and who are otherwise healthy, with a BMI below 33 and who score
        >23 performance points on Mini-mental state examination (MMSE).
      
Biospecimen description: 
      Whoole blood from which PBMCs (Peripheral Blood Monocytic Cells), plasma, serum will be
      stored.
    
Keywords: Inflammation/physiopathology, Immune System/immunology,; Neuroimmunomodulation/physiology, General Surgery; Heart Rate/physiology*Vagus Nerve/physiology*