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Neuroinflammation After Surgery

Perioperative neurocognitive disorders (PND) are now considered one of the most common postoperative complications among older adults. Patients may experience confusion, delirium, and irritability. Given the negative effects associated with this condition, it is important to understand its mechanism to better prevent and treat it. On the surface, it may appear that surgical trauma is the biggest player in the pathogenesis of PNDs; upon further study, the root cause is neuroinflammation, which is driven by the tissue injury inflicted during surgery.

Cellular damage caused by surgical trauma triggers endogenous molecules known as damage-associated molecular patterns (DAMPs) to activate inflammatory pathways to resolve the damage and bring the body back to homeostasis. Activation of these cells results in inflammation to many bodily organs, most notably, the brain.1

A key component of the inflammatory response is the activation of the complement system, in particular, C-reactive protein (CRP) and complement component 3 (C3).2 When researchers modeled the effects of orthopedic surgery in mice, C3 levels were significantly increased in hippocampal astrocytes and microglia after surgery. Blocking C3 receptors attenuated synapse loss in the hippocampus and improved hippocampal-dependent memory function, suggesting that the activation of the complement system in neuroinflammation because of surgery plays a prominent role in PND development.3

Surgical trauma also activates the coagulation cascade, starting with the fibrinolytic system, which converts fibrinogen to fibrin for blood clotting. If fibrin enters the CNS, it can bind to C3 receptors to further increase macrophage and microglia activation, which increases cognitive deficits.1,4 Data showed perivascular fibrin deposits could be found in the hippocampus just 24 hours after surgery4. In addition to neuroinflammation, these deposits have been associated with several neurologic disorders, including multiple sclerosis, traumatic brain injury, and Alzheimer’s Disease.

Research on neuroinflammation after surgery often points to alterations in the blood-brain barrier (BBB). This barrier exists to keep pathogens, ions, and various macromolecules out of the CNS, and neurotransmitters and nutrients in.5 After surgical trauma, inflammatory mediators induce BBB permeability, contributing to alterations in adhesion molecules, signaling pathways, and organ perfusion. Supporting the notion that BBB alterations have a pathogenic role in PND, a prospective cohort study showed patients who exhibited BBB injury were more likely to experience a longer period of surgery-induced neuroinflammation. BBB injury was also associated with periods of cognitive decline and brain dysfunction.6

Another mechanism through which neuroinflammation occurs in the postoperative state is microglia. These resident immune cells of the CNS are rapidly activated after surgical trauma. Commonly expressed on microglia is TREM2, an endogenous immune receptor whose signaling contributes to heightened microglial responses and increases in pro-inflammatory markers. Additionally, TREM2 has established mutations that are widely associated with aging and neurodegenerative pathology.1

The neuroinflammatory response to surgical trauma involves multiple molecular departments. Ideally, interventions can begin as soon as the trauma is inflicted, to reduce the downstream effects of inflammation. One potential therapeutic target is specialized pro-resolving lipid mediators (SPMs). SPMs can act as agonists to shorten the duration of acute inflammation and may play a role in regulating the molecular systems described above. Further research can identify other therapies that offer an effective approach to protecting the brain from overactivation of the immune system.

References

  1. Yang, Ting, et al. “Neuroinflammation after Surgery: From Mechanisms to Therapeutic Targets.” Nature Immunology, vol. 21, no. 11, Nov. 2020, pp. 1319–26. www.nature.com, https://doi.org/10.1038/s41590-020-00812-1
  2. Hecke, Friederike, et al. “Circulating Complement Proteins in Multiple Trauma Patients-Correlation with Injury Severity, Development of Sepsis, and Outcome.” Critical Care Medicine, vol. 25, no. 12, Dec. 1997, p. 2015. journals.lww.com, https://journals.lww.com/ccmjournal/abstract/1997/12000/circulating_complement_proteins_in_multiple_trauma.19.aspx
  3. Xiong, Chao, et al. “Complement Activation Contributes to Perioperative Neurocognitive Disorders in Mice.” Journal of Neuroinflammation, vol. 15, no. 1, Sept. 2018, p. 254. Springer Link, https://doi.org/10.1186/s12974-018-1292-4
  4. Terrando, Niccolò, et al. “Resolving Postoperative Neuroinflammation and Cognitive Decline.” Annals of Neurology, vol. 70, no. 6, Dec. 2011, pp. 986–95. DOI.org (Crossref), https://doi.org/10.1002/ana.22664
  5. Abbott, N. Joan, et al. “Structure and Function of the Blood–Brain Barrier.” Neurobiology of Disease, vol. 37, no. 1, Jan. 2010, pp. 13–25. ScienceDirect, https://doi.org/10.1016/j.nbd.2009.07.030
  6. Hughes, Christopher G., et al. “Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.” Critical Care Medicine, vol. 44, no. 9, Sept. 2016, pp. e809–17. PubMed Central, https://doi.org/10.1097/CCM.0000000000001739
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