Prolonged mechanical ventilation–induced neuroinflammation affects postoperative memory dysfunction in surgical mice

Abstract

IntroductionPatients undergoing surgery frequently develop neuropsychological disturbances, including cognitive decline or memory impairment, and routine clinical procedures such as mechanical ventilation (MV) may affect acute-phase brain outcome. We aimed to investigate the effect of the prolonged MV on postoperative memory dysfunction in surgical mice.MethodsMale C57BL/6 mice were randomly divided into the following three groups: (1) The control group (group C) comprised anesthetized, unventilated animals; (2) the surgery group (subgroups S1h, S3h and S6h) was unventilated animals that underwent surgery under general anesthesia; and (3) the MV group (subgroups MV1h, MV3h and MV6h) was made up of animals under MV for 1 hour, 3 hours or 6 hours after surgery. Separate cohorts of animals were tested for memory function with fear conditioning tests or were killed at 6 hours, 1 day or 3 days postsurgery or post-MV to examine levels systemic and hippocampal interleukin (IL)-1β, IL-6 and tumor necrosis factor α (TNFα), and assessed synaptic structure and microglial activation. Nuclear factor κB (NF-κB) p65, cytochrome c, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) activation were analyzed by Western blotting.ResultsThe MV6h group showed increased CD11b-immunopositive cells, synapse degeneration, cytochrome c release, cleaved caspase-3 and cleaved PARP-1 activation after surgery, as well as a decrease in freezing time after surgery. At 6 hours and 1 day post-MV, MV6h increased NF-κB activation and levels of systemic and hippocampal IL-1β, IL-6 and TNFα after surgery.ConclusionsProlonged MV after surgery further aggravates cognitive decline that may stem from upregulation of hippocampal IL-1β, IL-6 and TNFα, partially via activation of gliocytes in the surgical mouse hippocampus.

Harmful effects of mechanical ventilation on neurocognitive functions

“…Relevance of MV-induced alveolar stretching in brain damage is witnessed by production of cerebral beta-amyloid and Alzheimer’s disease-like brain degeneration (cerebral amyloid β peptide accumulation, neuroinflammation, and blood-brain barrier dysfunction) even after relatively “short-term MV” (after 4 h MV in mice)—as reported in a recent study published in Critical Care [8]. The PaO 2 /PaCO 2 abnormalities—including hypo and hyper O 2 and/or CO 2 that often represent the indication to establish MV and can persist during MV—might contribute to promote neuronal death, cerebral oxidative stress, and changes in brain blood flow that worsen brain damage [10, 11]. Increased systemic inflammatory mediators produced by the lungs during MV (“biotrauma”) have been detected in several preclinical studies and include TNF alpha, IL6, IL10, IL1 beta, MCP1, and MIP2, which have a proven neuroinflammatory role [4, 5, 7].…”

Mechanisms involved in brain dysfunction in mechanically ventilated critically ill patients: implications and therapeutics

“…Quílez et al described how MV induced differential c-fos expression in several areas in the brain, depending on the ventilatory pattern, tidal volume (VT) and level of PEEP, thus supporting the hypothesis that an iatrogenic effect of MV may affect the brain (14,18). Chen et al found that prolonged MV (6 h) in mice induced cognitive decline and increased activation of microgliosis and apoptotic cascades after surgery, thus indicating the detrimental effects of prolonged MV in the brain (19). González-López et al identified a novel mechanism driven via vagal and dopaminergic pathways that triggers hippocampal apoptosis in response to lung stretch in mice undergoing MV (20).…”

Perioperative neurocognitive dysfunction: thinking from the gut?

“…In addition, during cardiac surgery, extracorporeal circulation, temperature management, anaesthetic dose, tissue ischaemia-reperfusion, regulation of cerebral blood flow, and oxygen saturation may all cause neuroinflammation and cognitive impairment [ 145 ]. Intraoperative and postoperative long-term mechanical ventilation increase the expression of peripheral and hippocampal inflammatory cells, activation of the apoptotic cascade, and reactive hyperplasia of the microglia by activating the vagus nerve and triggering type 2 dopamine receptors, which further aggravates cognitive decline [ 146 , 147 ].…”