The White Blood Cell Reactivity Following Surgical Trauma and Associated Regulatory Mechanisms.

Overview

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.

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.

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