Post-surgery Systemic Inflammation and Neuro-immune Interactions
Mots clés
Abstrait
La 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.
Rendez-vous
Dernière vérification: | 03/31/2019 |
Première soumission: | 01/09/2017 |
Inscription estimée soumise: | 02/12/2017 |
Première publication: | 02/15/2017 |
Dernière mise à jour soumise: | 04/10/2019 |
Dernière mise à jour publiée: | 04/15/2019 |
Date de début réelle de l'étude: | 12/31/2016 |
Date d'achèvement primaire estimée: | 11/30/2019 |
Date estimée d'achèvement de l'étude: | 11/30/2019 |
Condition ou maladie
Intervention / traitement
Other: Surgical patients
Phase
Groupes d'armes
Bras | Intervention / traitement |
---|---|
Surgical patients Cognitive testing, testing of heart rate variability and collection of blood samples | Other: Surgical patients Cognitive testing, testing of heart rate variability and collection of blood samples |
Critère d'éligibilité
Âges éligibles aux études | 45 Years À 45 Years |
Sexes éligibles à l'étude | Male |
Méthode d'échantillonnage | Probability Sample |
Accepte les bénévoles en santé | Oui |
Critères | Inclusion Criteria: - Male - BMI <33 - Age 45-75 - No significant neurological, cardiovascular or rheumatic diseases - Mini-mental state examination (MMSE) >23 Exclusion Criteria: - Unable to understand informed concent - Medication with Statins, beta blockers or immunomodulatory drugs |
Résultat
Mesures des résultats primaires
1. TNF alpha in blood [After LPS provocation within 4 hours]
Mesures des résultats secondaires
1. Markers of neuroinflammation in peripheral blood [Before surgery and up to 6 months after surgery]
2. Heart rate variability [Before surgery and up to 6 months after surgery]
3. Cognitive testing using the International Study of Post-Operative Cognitive Dysfunction [Before surgery and up to 6 months after surgery]