Neurotox Res. 2021 Apr;39(2):489-503. doi: 10.1007/s12640-020-00270-5. Epub 2020 Sep 02.
Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches.
Neurotoxicity research
Ming Gu, Xiang-Lin Mei, Ya-Nan Zhao
Affiliations
Affiliations
- Department of Emergency and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, China.
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China.
- Neurology Department, China-Japan Union Hospital of Jilin University, Changchun, 130000, People's Republic of China. [email protected].
PMID: 32876918
DOI: 10.1007/s12640-020-00270-5
Abstract
Sepsis-associated cerebral dysfunction is complex pathophysiology, generated from primary infections that are developed elsewhere in the body. The neonates, elderly population and chronically ill and long-term hospitalized patients are predominantly vulnerable to sepsis and related cerebral damage. Generally, electrophysiological recordings, severity and sedation scales, computerized imaging and spectroscopy techniques are used for its detection and diagnosis. About the underlying mechanisms, enhanced blood-brain barrier permeability and metalloprotease activity, tight junction protein loss and endothelial cell degeneration promote the influx of inflammatory and toxic mediators into the brain, triggering cerebrovascular damage. An altered neutrophil count and phenotype further dysregulate the normal neuroimmune responses and neuroendocrine stability via modulated activation of protein kinase C-delta, nuclear factor kappa-B and sphingolipid signaling. Glial activation, together with pro-inflammatory cytokines and chemokines and the Toll-like receptor, destabilize the immune system. Moreover, superoxides and hydroperoxides generate oxidative stress and perturb mitochondrial dynamics and ATP synthesis, propagating neuronal injury cycle. Activated mitochondrial apoptotic pathway, characterized by increased caspase-3 and caspase-9 cleavage and Bax/Bcl2 ratio in the hippocampal and cortical neurons, stimulate neurocognitive impairments. Additionally, altered LC3-II/I and P62/SQSTM1, p-mTOR, p-AMPK1 and p-ULK1 levels and dysregulated autophagosome-lysosome fusion decrease neuronal and glial energy homeostasis. The therapies and procedures for attenuating sepsis-induced brain damage include early resuscitation, cerebral blood flow autoregulation, implantable electric vagus nerve stimulation, antioxidants, statins, glucocorticoids, neuroimmune axis modulators and PKCδ inhibitors. The current review enumerates the pathophysiology of sepsis-induced brain damage, its diagnosis, the role of critical inducers and mediators and, ultimately, therapeutic measures attenuating cerebrovascular degeneration.
Keywords: Cerebrovascular damage; Cytokine imbalance; Metabolic changes; ROS; Sepsis-associated encephalopathy
References
- Abou Dagher G, El Khuri C, Chehadeh AA, Chami A, Bachir R (2017) Are patients with cancer with sepsis and bacteraemia at a higher risk of mortality? A retrospective chart review of patients presenting to a tertiary care centre in Lebanon. BMJ Open 7:e013502. https://doi.org/10.1136/bmjopen-2016-013502 - PubMed
- Agac D, Estrada LD, Maples R, Hooper LV, Farrar JD (2018) The beta2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion. Brain Behav Immun 74:176–185. https://doi.org/10.1016/j.bbi.2018.09.004 - PubMed
- Agapito Fonseca J, Gameiro J, Marques F, Lopes JA (2020) Timing of initiation of renal replacement therapy in sepsis-associated acute kidney injury. J Clin Med 9:9. https://doi.org/10.3390/jcm9051413 - PubMed
- Barichello T et al (2007a) Antioxidant treatment prevented late memory impairment in an animal model of sepsis. Crit Care Med 35:2186–2190. https://doi.org/10.1097/01.ccm.0000281452.60683.96 - PubMed
- Barichello T et al (2007b) Behavioral deficits in sepsis-surviving rats induced by cecal ligation and perforation. Braz J Med Biol Res 40:831–837. https://doi.org/10.1590/s0100-879x2007000600013 - PubMed
- Barone E et al (2011) Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: a novel mechanism of action. Pharmacol Res 63:172–180. https://doi.org/10.1016/j.phrs.2010.12.007 - PubMed
- Bedirli N, Bagriacik EU, Yilmaz G, Ozkose Z, Kavutcu M (2018) Sevoflurane exerts brain-protective effects against sepsis-associated encephalopathy and memory impairment through caspase 3/9 and Bax/Bcl signaling pathway in a rat model of sepsis. J Int Med Res 46:2828–2842. https://doi.org/10.1177/0300060518773265 - PubMed
- Biff D et al (2013) Correlation of acute phase inflammatory and oxidative markers with long-term cognitive impairment in sepsis survivors rats. Shock 40:45–48. https://doi.org/10.1097/SHK.0b013e3182959cfa - PubMed
- Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Jones I, Towner RA, Castro-Faria-Neto HC (2010) Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 30:440–448. https://doi.org/10.1038/jcbfm.2009.215 - PubMed
- Bragin DE, Statom GL, Yonas H, Dai X, Nemoto EM (2014) Critical cerebral perfusion pressure at high intracranial pressure measured by induced cerebrovascular and intracranial pressure reactivity. Crit Care Med 42:2582–2590. https://doi.org/10.1097/CCM.0000000000000655 - PubMed
- Candel FJ et al (2005) Bacteremia and septic shock after solid-organ transplantation. Transplant Proc 37:4097–4099. https://doi.org/10.1016/j.transproceed.2005.09.181 - PubMed
- Cao C, Gao T, Cheng M, Xi F, Zhao C (2017) Mild hypothermia ameliorates muscle wasting in septic rats associated with hypothalamic AMPK-induced autophagy and neuropeptides. Biochem Biophys Res Commun 490:882–888. https://doi.org/10.1016/j.bbrc.2017.06.135 - PubMed
- Cebey-Lopez M et al (2016) Bacteremia in children hospitalized with respiratory syncytial virus iinfection. PLoS One 11:e0146599. https://doi.org/10.1371/journal.pone.0146599 - PubMed
- Chaudhry N, Duggal AK (2014) Sepsis associated encephalopathy. Adv Med 2014:762320–762316. https://doi.org/10.1155/2014/762320 - PubMed
- Chen Y, Lei Y, Mo LQ, Li J, Wang MH (2016) Electroacupuncture pretreatment with different waveforms prevents brain injury in rats subjected to cecal ligation and puncture via inhibiting microglial activation, and attenuating inflammation, oxidative stress and apoptosis. Brain Res Bull 127:248–259. https://doi.org/10.1016/j.brainresbull.2016.10.009 - PubMed
- Choi DW, Park JH, Lee SY, An SH (2018) Effect of hypothermia treatment on gentamicin pharmacokinetics in neonates with hypoxic-ischaemic encephalopathy: a systematic review and meta-analysis. J Clin Pharm Ther 43:484–492. https://doi.org/10.1111/jcpt.12711 - PubMed
- Chou CH et al (2017) Septicemia is associated with increased risk for dementia: a population-based longitudinal study. Oncotarget 8:84300–84308. https://doi.org/10.18632/oncotarget.20899 - PubMed
- Comim CM et al (2011) Alterations in inflammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res 36:304–311. https://doi.org/10.1007/s11064-010-0320-2 - PubMed
- Comim CM, Barichello T, Grandgirard D, Dal-Pizzol F, Quevedo J (2013) Caspase-3 mediates in part hippocampal apoptosis in sepsis. Mol Neurobiol 47:394–398. https://doi.org/10.1007/s12035-012-8354-x - PubMed
- Comim CM et al (2017) Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis. J Neuroimmunol 305:167–171. https://doi.org/10.1016/j.jneuroim.2017.02.001 - PubMed
- Couraud PO (1998) Infiltration of inflammatory cells through brain endothelium. Pathol Biol (Paris) 46:176–180 - PubMed
- Crippa IA, Subirà C, Vincent JL, Fernandez RF, Hernandez SC, Cavicchi FZ, Creteur J, Taccone FS (2018) Impaired cerebral autoregulation is associated with brain dysfunction in patients with sepsis. Crit Care 22:327. https://doi.org/10.1186/s13054-018-2258-8 - PubMed
- Davies DC (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646. https://doi.org/10.1046/j.1469-7580.2002.00065.x - PubMed
- Denstaedt SJ et al (2018) S100A8/A9 drives neuroinflammatory priming and protects against anxiety-like behavior after sepsis. J Immunol 200:3188–3200. https://doi.org/10.4049/jimmunol.1700834 - PubMed
- Doll DN, Hu H, Sun J, Lewis SE, Simpkins JW (2015) Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier. Stroke 46:1681–1689. https://doi.org/10.1161/STROKEAHA.115.009099 - PubMed
- Ehlenbach WJ, Sonnen JA, Montine TJ, Larson EB (2019) Association between sepsis and microvascular brain injury. Crit Care Med 47:1531–1538. https://doi.org/10.1097/CCM.0000000000003924 - PubMed
- Erikson K, Tuominen H, Vakkala M, Liisanantti JH, Karttunen T (2020) Brain tight junction protein expression in sepsis in an autopsy series. Crit Care 24:385. https://doi.org/10.1186/s13054-020-03101-3 - PubMed
- Estenssoro E et al (2019) Health inequities in the diagnosis and outcome of sepsis in Argentina: a prospective cohort study. Crit Care 23:250. https://doi.org/10.1186/s13054-019-2522-6 - PubMed
- Exline MC, Crouser ED (2008) Mitochondrial mechanisms of sepsis-induced organ failure. Front Biosci 13:5030–5041 - PubMed
- Fang J, Lian Y, Xie K, Cai S, Wen P (2014) Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy. Neurol Sci 35:283–288. https://doi.org/10.1007/s10072-013-1508-4 - PubMed
- Freund HR, Muggia-Sullam M, Peiser J, Melamed E (1985) Brain neurotransmitter profile is deranged during sepsis and septic encephalopathy in the rat. J Surg Res 38:267–271. https://doi.org/10.1016/0022-4804(85)90037-x - PubMed
- Freund HR, Muggia-Sullam M, LaFrance R, Holroyde J, Fischer JE (1986) Regional brain amino acid and neurotransmitter derangements during abdominal sepsis and septic encephalopathy in the rat. The effect of amino acid infusions. Arch Surg 121:209–216. https://doi.org/10.1001/archsurg.1986.01400020095011 - PubMed
- Gaspar-da-Costa P, Reimao S, Braz S, Santos JM, Victorino RMM (2017) Disseminated necrotizing leukoencephalopathy complicating septic shock in an immunocompetent patient case. Rep Crit Care 2017:1092537–1092534. https://doi.org/10.1155/2017/1092537 - PubMed
- Gattinoni L, Vasques F, Camporota L, Meessen J, Romitti F, Pasticci I, Duscio E, Vassalli F, Forni LG, Payen D, Cressoni M, Zanella A, Latini R, Quintel M, Marini JJ (2019) Understanding lactatemia in human sepsis. Potential impact for early management. Am J Respir Crit Care Med 200:582–589. https://doi.org/10.1164/rccm.201812-2342OC - PubMed
- Ghosh PS, Kwon C, Klein M, Corder J, Ghosh D (2014) Neurologic complications following pediatric renal transplantation. J Child Neurol 29:793–798. https://doi.org/10.1177/0883073813490074 - PubMed
- Goldim MP et al (2019) Oxidative stress in the choroid plexus contributes to blood-cerebrospinal fluid barrier disruption during sepsis development. Microvasc Res 123:19–24. https://doi.org/10.1016/j.mvr.2018.12.001 - PubMed
- Gyawali B, Ramakrishna K, Dhamoon AS (2019) Sepsis: the evolution in definition, pathophysiology, and management. SAGE Open Med 7:2050312119835043. https://doi.org/10.1177/2050312119835043 - PubMed
- Honig G et al (2016) Blood-brain barrier deterioration and hippocampal gene expression in polymicrobial sepsis: an evaluation of endothelial MyD88 and the vagus nerve. PLoS One 11:e0144215. https://doi.org/10.1371/journal.pone.0144215 - PubMed
- Honig A, Eliahou R, Auriel E (2017) Confined anterior cerebral artery infarction manifesting as isolated unilateral axial weakness. J Neurol Sci 373:18–20. https://doi.org/10.1016/j.jns.2016.11.061 - PubMed
- Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR (2016) Sepsis and septic shock. Nat Rev Dis Primers 2:16045. https://doi.org/10.1038/nrdp.2016.45 - PubMed
- Huang M, Liu C, Hu Y, Wang P, Ding M (2014) Gamma-secretase inhibitor DAPT prevents neuronal death and memory impairment in sepsis associated encephalopathy in septic rats. Chin Med J 127:924–928 - PubMed
- Ince C, Mayeux PR, Nguyen T, Gomez H, Kellum JA, Ospina-Tascón GA, Hernandez G, Murray P, de Backer D, ADQI XIV Workgroup (2016) The endothelium in sepsis. Shock 45:259–270. https://doi.org/10.1097/SHK.0000000000000473 - PubMed
- Jeppsson B, Freund HR, Gimmon Z, James JH, von Meyenfeldt MF (1981) Blood-brain barrier derangement in sepsis: cause of septic encephalopathy? Am J Surg 141:136–142. https://doi.org/10.1016/0002-9610(81)90026-x - PubMed
- Kido K, Shindo Y, Toda S, Masaki E (2019) Expression of beta-endorphin in peripheral tissues after systemic administration of lipopolysaccharide as a model of endotoxic shock in mice. Ann Endocrinol (Paris) 80:117–121. https://doi.org/10.1016/j.ando.2018.06.001 - PubMed
- Kim KS (2006) Microbial translocation of the blood-brain barrier. Int J Parasitol 36:607–614. https://doi.org/10.1016/j.ijpara.2006.01.013 - PubMed
- Kuperberg SJ, Wadgaonkar R (2017) Sepsis-associated encephalopathy: the blood-brain barrier and the sphingolipid rheostat. Front Immunol 8:597. https://doi.org/10.3389/fimmu.2017.00597 - PubMed
- Lee EJ et al (2014) Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-alpha activation. J Immunol 193:2384–2393. https://doi.org/10.4049/jimmunol.1303240 - PubMed
- Leow-Dyke S et al (2012) Neuronal Toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. J Neuroinflammation 9:230. https://doi.org/10.1186/1742-2094-9-230 - PubMed
- Li Y, Su Y, Qu Y, Mu D, Li X (2016) Autophagy in hippocampal nerve cells from rats with sepsis-associated encephalopathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban 41:571–577. https://doi.org/10.11817/j.issn.1672-7347.2016.06.004 - PubMed
- Li Y, Wang F, Luo Y (2017) Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1-independent autophagy in mice. J Surg Res 207:181–189. https://doi.org/10.1016/j.jss.2016.08.080 - PubMed
- Lidwell OM, Lowbury EJ, Whyte W, Blowers R, Stanley SJ (1984) Infection and sepsis after operations for total hip or knee-joint replacement: influence of ultraclean air, prophylactic antibiotics and other factors. J Hyg (Lond) 93:505–529. https://doi.org/10.1017/s0022172400065098 - PubMed
- Lipowsky HH (2012) The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases. Ann Biomed Eng 40:840–848. https://doi.org/10.1007/s10439-011-0427-x - PubMed
- Liu W, Guo J, Mu J, Tian L, Zhou D (2017) Rapamycin protects sepsis-induced cognitive impairment in mouse hippocampus by enhancing autophagy. Cell Mol Neurobiol 37:1195–1205. https://doi.org/10.1007/s10571-016-0449-x - PubMed
- Lu H, Wen D, Wang X, Gan L, du J, Sun J, Zeng L, Jiang J, Zhang A (2019) Host genetic variants in sepsis risk: a field synopsis and meta-analysis. Crit Care 23:26. https://doi.org/10.1186/s13054-019-2313-0 - PubMed
- Lyu X, Cong Z, Li D, Tao Y, Zhu X (2018) Effect mechanism of alpha-adrenoceptor on sepsis-induced acute respiratory distress syndrome. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 30:83–87. https://doi.org/10.3760/cma.j.issn.2095-4352.2018.01.016 - PubMed
- Ma Y, Matsuwaki T, Yamanouchi K, Nishihara M (2017) Glucocorticoids suppress the protective effect of cyclooxygenase-2-related signaling on hippocampal neurogenesis under acute immune stress. Mol Neurobiol 54:1953–1966. https://doi.org/10.1007/s12035-016-9766-9 - PubMed
- Mai C, Qiu L, Zeng Y, Jian HG (2019) LncRNA Lethe protects sepsis-induced brain injury via regulating autophagy of cortical neurons. Eur Rev Med Pharmacol Sci 23:4858–4864. https://doi.org/10.26355/eurrev_201906_18073 - PubMed
- Maiden MJ, Finnis ME, Peake S, McRae S, Delaney A (2018) Haemoglobin concentration and volume of intravenous fluids in septic shock in the ARISE trial. Crit Care 22:118. https://doi.org/10.1186/s13054-018-2029-6 - PubMed
- Manfredini A et al (2019) Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model. Clin Sci (Lond) 133:1993–2004. https://doi.org/10.1042/CS20190351 - PubMed
- Manou-Stathopoulou V, Korbonits M, Ackland GL (2019) Redefining the perioperative stress response: a narrative review. Br J Anaesth 123:570–583. https://doi.org/10.1016/j.bja.2019.08.011 - PubMed
- Matin A, Nawaz S, Jung SY (2018) Report: Effect of macrophage alone or primed with cytokines on Balamuthia mandrillaris interactions with human brain microvascular endothelial cells in vitro. Pak J Pharm Sci 31:2553–2559 - PubMed
- Merz TM, Pereira AJ, Schurch R, Schefold JC, Jakob SM (2017) Mitochondrial function of immune cells in septic shock: a prospective observational cohort study. PLoS One 12:e0178946. https://doi.org/10.1371/journal.pone.0178946 - PubMed
- Michelon C et al (2020) The role of secretase pathway in long-term brain inflammation and cognitive impairment in an animal model of severe sepsis. Mol Neurobiol 57:1159–1169. https://doi.org/10.1007/s12035-019-01808-1 - PubMed
- Michels M et al (2015) CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis. Mol Med 21:219–226. https://doi.org/10.2119/molmed.2015.00070 - PubMed
- Michels M, Ávila P, Pescador B, Vieira A, Abatti M, Cucker L, Borges H, Goulart AI, Junior CC, Barichello T, Quevedo J, Dal-Pizzol F (2019) Microglial cells depletion increases inflammation and modifies microglial phenotypes in an animal model of severe sepsis. Mol Neurobiol 56:7296–7304. https://doi.org/10.1007/s12035-019-1606-2 - PubMed
- Michels M, Abatti MR, Ávila P, Vieira A, Borges H, Carvalho Junior C, Wendhausen D, Gasparotto J, Tiefensee Ribeiro C, Moreira JCF, Gelain DP, Dal-Pizzol F (2020) Characterization and modulation of microglial phenotypes in an animal model of severe sepsis. J Cell Mol Med 24:88–97. https://doi.org/10.1111/jcmm.14606 - PubMed
- Mina F et al (2014) Il1-beta involvement in cognitive impairment after sepsis. Mol Neurobiol 49:1069–1076. https://doi.org/10.1007/s12035-013-8581-9 - PubMed
- Mohamud JA, Wu J, Jing Y, Wang Y (2018) Septic embolic stroke followed by hemorrhage and brain abscess in a patient with systemic infections: a case report and literature review. Case Rep Radiol 2018:4602352–4602355. https://doi.org/10.1155/2018/4602352 - PubMed
- Molnar L, Fulesdi B, Nemeth N, Molnar C (2018) Sepsis-associated encephalopathy: a review of literature. Neurol India 66:352–361. https://doi.org/10.4103/0028-3886.227299 - PubMed
- Morita S, Furube E, Mannari T, Okuda H, Tatsumi K (2015) Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain. Cell Tissue Res 359:865–884. https://doi.org/10.1007/s00441-014-2080-9 - PubMed
- Nagarjuna D, Mittal G, Dhanda RS, Gaind R, Yadav M (2018) Alarming levels of antimicrobial resistance among sepsis patients admitted to ICU in a tertiary care hospital in India - a case control retrospective study. Antimicrob Resist Infect Control 7:150. https://doi.org/10.1186/s13756-018-0444-8 - PubMed
- Nwafor DC, Brichacek AL, Mohammad AS, Griffith J, Lucke-Wold BP, Benkovic SA, Geldenhuys WJ, Lockman PR, Brown CM (2019) Targeting the blood-brain barrier to prevent sepsis-associated cognitive impairment. J Cent Nerv Syst Dis 11:1179573519840652. https://doi.org/10.1177/1179573519840652 - PubMed
- Olivieri R et al (2018) The additive effect of aging on sepsis-induced cognitive impairment and neuroinflammation. J Neuroimmunol 314:1–7. https://doi.org/10.1016/j.jneuroim.2017.11.014 - PubMed
- Padhi R, Kabi S, Panda BN, Jagati S (2018) Prognostic significance of nonthyroidal illness syndrome in critically ill adult patients with sepsis. Int J Crit Illn Inj Sci 8:165–172. https://doi.org/10.4103/IJCIIS.IJCIIS_29_17 - PubMed
- Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E (2018) Epidemiology and costs of sepsis in the United States-an analysis based on timing of diagnosis and severity level. Crit Care Med 46:1889–1897. https://doi.org/10.1097/CCM.0000000000003342 - PubMed
- Peeters B, Meersseman P, Vander Perre S, Wouters PJ, Debaveye Y (2018) ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study. Intensive Care Med 44:2048–2058. https://doi.org/10.1007/s00134-018-5427-y - PubMed
- Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP, Latil M, Matot B, Carlier PG, Latronico N, Huchet C, Lafoux A, Sharshar T, Ricchetti M, Chrétien F (2015) Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun 6:10145. https://doi.org/10.1038/ncomms10145 - PubMed
- Rudd KE et al (2020) Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 395:200–211. https://doi.org/10.1016/S0140-6736(19)32989-7 - PubMed
- Russell JA, Rush B, Boyd J (2018) Pathophysiology of septic shock. Crit Care Clin 34:43–61. https://doi.org/10.1016/j.ccc.2017.08.005 - PubMed
- Santos-Junior NN et al (2018) Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus. J Neuroimmunol 324:143–148. https://doi.org/10.1016/j.jneuroim.2018.08.013 - PubMed
- Schroeder S et al (2001) The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 29:310–316. https://doi.org/10.1097/00003246-200102000-00017 - PubMed
- Schwalm MT et al (2014) Acute brain inflammation and oxidative damage are related to long-term cognitive deficits and markers of neurodegeneration in sepsis-survivor rats. Mol Neurobiol 49:380–385. https://doi.org/10.1007/s12035-013-8526-3 - PubMed
- Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schäfers M, Kummer MP, Klockgether T, Heneka MT (2008) Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 5:38. https://doi.org/10.1186/1742-2094-5-38 - PubMed
- Sendemir E, Kafa IM, Schafer HH, Jirikowski GF (2013) Altered oxytocinergic hypothalamus systems in sepsis. J Chem Neuroanat 52:44–48. https://doi.org/10.1016/j.jchemneu.2013.05.001 - PubMed
- Singer M (2014) The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5:66–72. https://doi.org/10.4161/viru.26907 - PubMed
- Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T (2013) Understanding brain dysfunction in sepsis. Ann Intensive Care 3:15. https://doi.org/10.1186/2110-5820-3-15 - PubMed
- Sood A, Abdollah F, Sammon JD, Arora N, Weeks M, Peabody JO, Menon M, Trinh QD (2017) Postoperative sepsis prediction in patients undergoing major cancer surgery. J Surg Res 209:60–69. https://doi.org/10.1016/j.jss.2016.09.059 - PubMed
- Su Y, Qu Y, Zhao F, Li H, Mu D (2015) Regulation of autophagy by the nuclear factor kappaB signaling pathway in the hippocampus of rats with sepsis. J Neuroinflammation 12:116. https://doi.org/10.1186/s12974-015-0336-2 - PubMed
- Taccone FS et al (2014) Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis. Crit Care Med 42:e114–e122. https://doi.org/10.1097/CCM.0b013e3182a641b8 - PubMed
- Tang Y, Soroush F, Sun S, Liverani E, Langston JC, Yang Q, Kilpatrick LE, Kiani MF (2018) Protein kinase C-delta inhibition protects blood-brain barrier from sepsis-induced vascular damage. J Neuroinflammation 15:309. https://doi.org/10.1186/s12974-018-1342-y - PubMed
- Terrando N et al (2010) The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care 14:R88. https://doi.org/10.1186/cc9019 - PubMed
- Towner RA et al (2013) In vivo detection of free radicals in mouse septic encephalopathy using molecular MRI and immuno-spin trapping. Free Radic Biol Med 65:828–837. https://doi.org/10.1016/j.freeradbiomed.2013.08.172 - PubMed
- Tu Q, Cao H, Zhong W, Ding B, Tang X (2014) Atorvastatin protects against cerebral ischemia/reperfusion injury through anti-inflammatory and antioxidant effects. Neural Regen Res 9:268–275. https://doi.org/10.4103/1673-5374.128220 - PubMed
- Turillazzi E, Fineschi V, Palmiere C, Sergi C (2016) Cardiovascular involvement in sepsis mediators. Inflamm 2016:8584793–8584793. https://doi.org/10.1155/2016/8584793 - PubMed
- Uchimido R, Schmidt EP, Shapiro NI (2019) The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 23:16. https://doi.org/10.1186/s13054-018-2292-6 - PubMed
- Udy AA, Finnis M, Jones D, Delaney A, Macdonald S, Bellomo R, Peake S, ARISE Investigators (2019) Incidence, patient characteristics, mode of drug delivery, and outcomes of septic shock patients treated with vasopressors in the arise trial. Shock 52:400–407. https://doi.org/10.1097/SHK.0000000000001281 - PubMed
- Vardon Bounes F, Mémier V, Marcaud M, Jacquemin A, Hamzeh-Cognasse H, Garcia C, Series J, Sié P, Minville V, Gratacap MP, Payrastre B (2018) Platelet activation and prothrombotic properties in a mouse model of peritoneal sepsis. Sci Rep 8:13536. https://doi.org/10.1038/s41598-018-31910-8 - PubMed
- Verboom DM, Frencken JF, Ong DSY, Horn J, van der Poll T, Bonten MJM, Cremer OL, Klein Klouwenberg PMC (2019) Robustness of sepsis-3 criteria in critically ill patients. J Intensive Care 7:46. https://doi.org/10.1186/s40560-019-0400-6 - PubMed
- Walsh KM, Courtney CL (1998) Nasal toxicity of CI-959, a novel anti-inflammatory drug, in Wistar rats and beagle dogs. Toxicol Pathol 26:717–723. https://doi.org/10.1177/019262339802600601 - PubMed
- Wang P, Ba ZF, Chaudry IH (1991) Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output. Arch Surg 126:219–224. https://doi.org/10.1001/archsurg.1991.01410260109015 - PubMed
- Wang P, Ba ZF, Chaudry IH (1997) Mechanism of hepatocellular dysfunction during early sepsis. Key role of increased gene expression and release of proinflammatory cytokines tumor necrosis factor and interleukin-6. Arch Surg 132:364–369; discussion 369-370. https://doi.org/10.1001/archsurg.1997.01430280038005 - PubMed
- Wang GB, Ni YL, Zhou XP, Zhang WF (2014) The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis. Mol Cell Biochem 385:125–132. https://doi.org/10.1007/s11010-013-1821-5 - PubMed
- Wang DW, Yin YM, Yao YM (2016) Vagal modulation of the inflammatory response in sepsis. Int Rev Immunol 35:415–433. https://doi.org/10.3109/08830185.2015.1127369 - PubMed
- Wang Z, Ren J, Wang G, Liu Q, Guo K (2017) Association between diabetes mellitus and outcomes of patients with sepsis: a meta-analysis. Med Sci Monit 23:3546–3555. https://doi.org/10.12659/msm.903144 - PubMed
- Wang P, Hu Y, Yao D, Li Y (2018) Omi/HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy cell. Physiol Biochem 49:2163–2173. https://doi.org/10.1159/000493819 - PubMed
- Weigand MA, Volkmann M, Schmidt H, Martin E, Bohrer H (2000) Neuron-specific enolase as a marker of fatal outcome in patients with severe sepsis or septic shock. Anesthesiology 92:905–907. https://doi.org/10.1097/00000542-200003000-00057 - PubMed
- Winder TR, Minuk GY, Sargeant EJ, Seland TP (1988) Gamma-Aminobutyric acid (GABA) and sepsis-related encephalopathy. Can J Neurol Sci 15:23–25. https://doi.org/10.1017/s0317167100027128 - PubMed
- Zaid Y, Rajeh A, Hosseini Teshnizi S, Alqarn A, Tarkesh F (2019) Epidemiologic features and risk factors of sepsis in ischemic stroke patients admitted to intensive care: a prospective cohort study. J Clin Neurosci 69:245–249. https://doi.org/10.1016/j.jocn.2019.07.031 - PubMed
- Zampieri FG, Park M, Machado FS, Azevedo LC (2011) Sepsis-associated encephalopathy: not just delirium Clinics (Sao Paulo). 66:1825–1831. https://doi.org/10.1590/s1807-59322011001000024 - PubMed
- Zhang A et al (2018a) Genetic contribution of suppressor of cytokine signalling polymorphisms to the susceptibility to infection after traumatic injury. Clin Exp Immunol 194:93–102. https://doi.org/10.1111/cei.13160 - PubMed
- Zhang X, Yan F, Feng J, Qian H, Cheng Z, Yang Q, Wu Y, Zhao Z, Li A, Xiao H (2018b) Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-kappaB pathway. PLoS One 13:e0196897. https://doi.org/10.1371/journal.pone.0196897 - PubMed
- Zhou R, Sun X, Li Y, Huang Q, Qu Y (2019) Low-dose Dexamethasone Increases Autophagy in Cerebral Cortical Neurons of Juvenile Rats with Sepsis Associated Encephalopathy. Neuroscience 419:83–99. https://doi.org/10.1016/j.neuroscience.2019.09.020 - PubMed
- Zhou RX, Li YY, Qu Y, Huang Q, Sun XM (2020) Regulation of hippocampal neuronal apoptosis and autophagy in mice with sepsis-associated encephalopathy by immunity-related GTPase M1 CNS. Neurosci Ther 26:177–188. https://doi.org/10.1111/cns.13229 - PubMed
- Zrzavy T, Hoftberger R, Berger T, Rauschka H, Butovsky O (2019) Pro-inflammatory activation of microglia in the brain of patients with sepsis. Neuropathol Appl Neurobiol 45:278–290. https://doi.org/10.1111/nan.12502 - PubMed
Publication Types