Post-surgery Systemic Inflammation and Neuro-immune Interactions
Condition: Inflammation; Surgery
MeSH terms: Inflammation
Study type: Observational

Summary: 
      The aim is to map the inflammatory response after surgery and further investigate the
      mechanisms by which inflammation is regulated. The inflammatory cascade is pivotal in
      protecting organisms against invading pathogens and in enabling healing of damaged tissues,
      yet the cascade itself may be harmful to the organism when excessive (e g septic chock).

      The increased immune-reactivity after trauma, such as surgery, is furthermore associated with
      post-operative declines in memory and learning capacity, a condition likely related to the
      notion of "sickness behavior". The effects on the brain after surgery and the associated
      neuro-immune crosstalk will now be investigated with focus on changes in immune reactivity in
      peripheral blood after surgery.
    

Detailed description: 
      Surgical trauma causes release of damage-associated molecular patterns (DAMPs) and other
      alarmines (e.g. high mobility group box (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. tumor necrosis factor alfa (TNFa),
      interleukin (IL)-1B, IL-6, IL-8, IL-10) being dependent on intracellular activation of
      nuclear factor nuclear factor kappa beta (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.

      A recent study has mapped periphery-to-brain-signaling after surgical trauma and the impact
      of major surgical trauma on the human brain by serial positron emission tomography
      (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 lipid polysaccharide (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 postoperative cognitive
      dysfunction (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.
    

Intervention name(s): Observational study of patients undergoing surgery
Intervention type(s): Other
Intervention description(s): Cognitive testing, testing of heart rate variability and collection of blood samples
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients undergoing elective abdominal surgery
      
Biospecimen description: 
      Blood samples