Improved Survival and Neurological Outcomes After Cardiopulmonary Resuscitation in Toll-like Receptor 4-mutant Mice

Overview

Journal Chin Med J (Engl)

Specialty General Medicine

Date 2015 Sep 30

PMID 26415804

Citations 3

Authors

Li Xu

Qing Zhang

Qing-Song Zhang

Qian Li

Ji-Yuan Han

Peng Sun

Affiliations

Soon will be listed here.

Abstract

Background: Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system and noninfectious immune responses. It has been reported that TLR4 participates in the pathological course of ischemia/reperfusion (I/R) injury. However, the role of TLR4 in the process of I/R injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is still unknown. In this study, we investigated the effects of TLR4 mutation on survival and neurological outcome in a mouse model of CA/CPR.

Methods: A model of potassium-induced CA was performed on TLR4-mutant mice (C3H/HeJ) and wild-type mice (C3H/HeN). After 3 min of untreated CA, resuscitation was attempted with chest compression, ventilation, and intravenous epinephrine. Behavioral tests were performed on mice on day 3 after CPR. The morphological changes in hippocampal neurons were assessed by light and electron microscopy. Expressions of TLR4 and intercellular adhesion molecule-1 (ICAM-1) were detected by Western blot. Levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) were measured with enzyme-linked immunosorbent assay (ELISA).

Results: On day 3 after resuscitation the overall mortality was 33.33% in C3H/HeJ group compared with 53.33% in C3H/HeN group (P < 0.05). And there was much higher central tendency in C3H/HeJ group than C3H/HeN group during open field test (P < 0.05). Meanwhile, the percentage of nonviable neurons was 21.16% in C3H/HeJ group compared with 53.11% in C3H/HeN group (P < 0.05). And there were significantly lower levels of hippocampal TNF-α and MPO in C3H/HeJ mice (TNF-α: 6.85±1.19 ng/mL, MPO: 0.33±0.11 U/g) than C3H/HeN mice (TNF-α: 11.36±2.12 ng/mL, MPO: 0.54±0.17 U/g) (all P < 0.01). CPR also significantly increased the expressions of TLR4 and ICAM-1 in C3H/HeN group. However, the expression of ICAM-1 was much lower in C3H/HeJ group than in C3H/HeN group after CPR (P < 0.01).

Conclusion: TLR4 signaling is involved in brain damage and in inflammation triggered by CA/CPR.

Citing Articles

Sodium butyrate attenuates microglia-mediated neuroinflammation by modulating the TLR4/MyD88/NF-κB pathway and microbiome-gut-brain axis in cardiac arrest mice.

Sun J, Lu L, Lian Y, Xu S, Zhu Y, Wu Y Mol Brain. 2025; 18(1):13.

PMID: 39962509 PMC: 11834616. DOI: 10.1186/s13041-025-01179-w.

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation.

Bergt S, Grub A, Mueller M, Bajorat R, Barilar I, Vollmar B PLoS One. 2019; 14(8):e0220404.

PMID: 31369614 PMC: 6675321. DOI: 10.1371/journal.pone.0220404.

RNase alleviates neurological dysfunction in mice undergoing cardiac arrest and cardiopulmonary resuscitation.

Ma Y, Chen C, Zhang S, Wang Q, Chen H, Dong Y Oncotarget. 2017; 8(32):53084-53099.

PMID: 28881795 PMC: 5581094. DOI: 10.18632/oncotarget.18088.

Effect of Splenic Regulatory T-cell Apoptosis on the Postresuscitation Immune Dysfunction in a Porcine Model.

Gu W, Zhang Q, Li C Chin Med J (Engl). 2016; 129(13):1577-83.

PMID: 27364795 PMC: 4931265. DOI: 10.4103/0366-6999.184461.

References

Neumar R, Nolan J, Adrie C, Aibiki M, Berg R, Bottiger B . Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on.... Circulation. 2008; 118(23):2452-83. DOI: 10.1161/CIRCULATIONAHA.108.190652. View

Wang Y, Ge P, Zhu Y . TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediators Inflamm. 2013; 2013:124614. PMC: 3706022. DOI: 10.1155/2013/124614. View

Aderem A, Ulevitch R . Toll-like receptors in the induction of the innate immune response. Nature. 2000; 406(6797):782-7. DOI: 10.1038/35021228. View

Laver S, Farrow C, Turner D, Nolan J . Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004; 30(11):2126-8. DOI: 10.1007/s00134-004-2425-z. View

Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X . Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282(5396):2085-8. DOI: 10.1126/science.282.5396.2085. View

Cao C, Yang Q, Lv F, Cui J, Fu H, Wang J . Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun. 2006; 353(2):509-14. DOI: 10.1016/j.bbrc.2006.12.057. View

Sui B, Li Y, Ma L . Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation. Exp Ther Med. 2014; 8(4):1301-1307. PMC: 4151659. DOI: 10.3892/etm.2014.1876. View

Caso J, Pradillo J, Hurtado O, Lorenzo P, Moro M, Lizasoain I . Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 2007; 115(12):1599-608. DOI: 10.1161/CIRCULATIONAHA.106.603431. View

Spencer S, Mouihate A, Pittman Q . Peripheral inflammation exacerbates damage after global ischemia independently of temperature and acute brain inflammation. Stroke. 2007; 38(5):1570-7. DOI: 10.1161/STROKEAHA.106.476507. View

10.

Kawamoto E, Cutler R, Rothman S, Mattson M, Camandola S . TLR4-dependent metabolic changes are associated with cognitive impairment in an animal model of type 1 diabetes. Biochem Biophys Res Commun. 2013; 443(2):731-7. PMC: 3916215. DOI: 10.1016/j.bbrc.2013.12.039. View

11.

Rymaszewski A, Tate E, Yimbesalu J, Gelman A, Jarzembowski J, Zhang H . The role of neutrophil myeloperoxidase in models of lung tumor development. Cancers (Basel). 2014; 6(2):1111-27. PMC: 4074819. DOI: 10.3390/cancers6021111. View

12.

Deng G, Yonchek J, Quillinan N, Strnad F, Exo J, Herson P . A novel mouse model of pediatric cardiac arrest and cardiopulmonary resuscitation reveals age-dependent neuronal sensitivities to ischemic injury. J Neurosci Methods. 2013; 222:34-41. PMC: 3919447. DOI: 10.1016/j.jneumeth.2013.10.015. View

13.

Norman G, Zhang N, Morris J, Karelina K, Berntson G, DeVries A . Social interaction modulates autonomic, inflammatory, and depressive-like responses to cardiac arrest and cardiopulmonary resuscitation. Proc Natl Acad Sci U S A. 2010; 107(37):16342-7. PMC: 2941316. DOI: 10.1073/pnas.1007583107. View

14.

Sladojevic N, Stamatovic S, Keep R, Grailer J, Sarma J, Ward P . Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury. Neurobiol Dis. 2014; 67:57-70. PMC: 4273560. DOI: 10.1016/j.nbd.2014.03.010. View

15.

Lindsberg P, Grau A . Inflammation and infections as risk factors for ischemic stroke. Stroke. 2003; 34(10):2518-32. DOI: 10.1161/01.STR.0000089015.51603.CC. View

16.

Jin R, Yang G, Li G . Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010; 87(5):779-89. PMC: 2858674. DOI: 10.1189/jlb.1109766. View

17.

Neigh G, Kofler J, Meyers J, Bergdall V, Perle K, Traystman R . Cardiac arrest/cardiopulmonary resuscitation increases anxiety-like behavior and decreases social interaction. J Cereb Blood Flow Metab. 2004; 24(4):372-82. PMC: 1363744. DOI: 10.1097/00004647-200404000-00002. View

18.

Beutler B . Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004; 430(6996):257-63. DOI: 10.1038/nature02761. View

19.

Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N . Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007; 117(4):e25-146. DOI: 10.1161/CIRCULATIONAHA.107.187998. View

20.

Niemann J, Rosborough J, Youngquist S, Shah A, Lewis R, Phan Q . Cardiac function and the proinflammatory cytokine response after recovery from cardiac arrest in swine. J Interferon Cytokine Res. 2009; 29(11):749-58. PMC: 3096522. DOI: 10.1089/jir.2009.0035. View