Systemic inflammation and neuroimmunity in surgical trauma

Abstract

<p dir="ltr">Tissue injury due to surgery or trauma initiates the release of damage associated molecular patterns (DAMPs), which in turn triggers a cascade of immune cell activation and the release of inflammatory mediators. Although the inflammatory process often begins locally, it may grow out of local capacities and require systemic involvement. While this potent evolutionary response is aimed to limit damage and facilitate repair, it must be carefully regulated to prevent further harm. Patients undergoing elective surgery may develop several complications arising from excessive or impaired immune responses such as cognitive impairment, systemic inflammatory response syndrome (SIRS) or infection. Neuroimmune regulatory mechanisms, based on autonomic nervous control of peripheral inflammation, have been found to attenuate and resolve inflammation in acute and chronic experimental as well as clinical settings. This thesis aims to explore the role and relevance of 'neuroimmunity', a concept involving neural sensing and regulation of immune responses, in the context of surgical trauma.</p><p dir="ltr">Paper I explores the carotid body (CB) as a putative sensor and mediator of systemic inflammation triggered by surgery. Rat CBs were excised and exposed ex vivo to DAMPs, such as high mobility group box protein 1 (HMGB1), S100A8/A9, or conditioned plasma obtained from a surgical model in rats. Release of neurotransmitters, indicating CB activation, as well as transcriptional changes were analyzed. Results show that CBs express DAMP receptors (RAGE, TLR4 and CXCR4), and that both DAMPs and conditioned plasma trigger CB neurotransmitter release and evoke multiple changes in CB gene expression.</p><p dir="ltr">Paper II is a temporal characterization of the molecular immune response to surgery, concurrent changes in heart rate variability (HRV) and cognitive capacity. Male patients (n=25) scheduled for abdominal surgery were sequentially evaluated before and up to 6 months after surgery. Blood samples and recordings of HRV were retrieved at multiple timepoints. Cognitive testing was performed pre-operatively and repeated 3-5 days and 6-8 weeks post- surgery. Cellular and molecular analyses revealed systemic molecular response patterns to surgery in line with previous experimental findings. Further, distinct patient-specific HRV-patterns were identified and these observations correlated with inflammatory protein trajectories in proteomic analyses.</p><p dir="ltr">Cognitive changes showed a trend toward significance, where patients with high HRV performed better cognitively compared to those with low HRV.</p><p dir="ltr">Paper III focuses on the systemic cellular response to surgery. Pre-operative (baseline) HRV and cellular immune status were assessed in male surgical patients (n=40) and followed with serial blood samples up to 6 months, complementing paper II. In-depth cellular and molecular analyses of the leukocyte proteomic response to lipopolysaccharide (LPS) ex vivo were performed. Temporal differences in subsets of polymorphonuclear cells (PMNs) and peripheral blood mononuclear cells (PBMCs) after surgery as well as changes in protein expression after surgery and whole blood LPS stimulation associated with baseline HRV.</p><p dir="ltr">In conclusion, the works of this thesis establish that the carotid body contains the molecular machinery necessary for sensing inflammation and transmitting inflammatory information to the brain. Furthermore, human studies demonstrate that heart rate variability (HRV) is a key patient characteristic associated with the inflammatory response to surgery, indicating the involvement of neuroimmune regulatory mechanisms in maintaining immune homeostasis after sterile trauma. A deeper understanding of temporal immune trajectories and their associated regulatory capacities is essential for guiding future patient- centered care and reducing the risk of immune-related complications following surgery.</p><h3>List of scientific papers</h3><p><br></p><p dir="ltr">I. The impact of damage-associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body.<br>Mkrtchian S, Kåhlin J, Gómez-Galán M, Ebberyd A, Yoshitake T, Schmidt S, Kehr J, <b>Hildenborg M,</b> Jonsson Fagerlund M, Erlandsson Harris H, Eriksson LI.</p><p dir="ltr">Exp Physiol. 2020 Sep;105(9):1634-1647 <br><a href="https://doi.org/10.1113/EP088705" target="_blank">https://doi.org/10.1113/EP088705<br><br></a></p><p dir="ltr">II. The neuroimmune response to surgery - an exploratory study of trauma-induced changes in innate immunity and heart rate variability.<br><b>Hildenborg M,</b> Kåhlin J, Granath F, Schening A, Granström A, Ebberyd A, Klevenvall L, Zetterberg H, Han J, Schlegel TT, Harris R, Harris HE, Eriksson LI.</p><p dir="ltr">Front Immunol. 2022 Jul 7;13:911744 <br><a href="https://doi.org/10.3389/fimmu.2022.911744" target="_blank">https://doi.org/10.3389/fimmu.2022.911744<br><br></a></p><p dir="ltr">III. Patient neuroimmune properties and the cellular immune response to surgical trauma.<br><b>Hildenborg M,</b> Filipovic I, Sun D, Kahlin J, Schening A, Granström A, Klevenvall L, Erlandsson Harris H, Schlegel TT, Bjorkstrom N, Eriksson LI.</p><p dir="ltr">[Manuscript]</p>