慢性脑低灌注性血管性认知损害患者血清p75神经营养素受体细胞外段水平及其与炎性因子的关系
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摘要
目的检测慢性脑低灌注性血管性认知损害(CCH-VCI)患者血清p75神经营养素受体细胞外段(p75NTR-ECD)水平,并探讨其与肿瘤坏死因子α(TNF-α)、白细胞介素(IL)-1β、IL-6的关系。方法选择海军军医大学(第二军医大学)长海医院2018年8月至12月收治的34例CCH-VCI患者,以及同期相同年龄段的36名中老年健康人和34例缺血性脑卒中患者作为研究对象。采用酶联免疫吸附试验测定3组研究对象的血清p75NTR-ECD、TNF-α、IL-1β、IL-6水平并进行组间比较。采用Spearman相关分析研究CCH-VCI患者血清p75NTR-ECD水平与TNF-α、IL-1β、IL-6水平的相关性。结果 CCH-VCI组血清p75NTR-ECD水平高于健康对照组和缺血性脑卒中组[(544.36(440.88,628.50)pg/mL vs 276.49(262.59,313.87)pg/mL、366.87(337.09,450.43)pg/mL],差异均有统计学意义(U=87.500、335.500,P均<0.05)。CCH-VCI组患者血清TNF-α、IL-1β、IL-6水平分别为196.02(141.20,280.35)pg/mL、68.23(60.79,91.94)pg/mL、51.04(40.24,65.26)pg/mL,缺血性脑卒中组分别为218.67(143.76,281.28)pg/mL、76.87(59.10,99.91)pg/mL、64.45(43.13,86.76)pg/mL,均分别高于健康对照组[分别为73.71(56.94,79.81)pg/mL、42.98(34.52,51.34)pg/mL、14.97(11.76,21.19)pg/mL],差异均有统计学意义(U=31.000、4.000,106.000、132.000,48.000、13.000;P均<0.05)。CCH-VCI患者血清p75NTR-ECD水平与 TNF-α水平存在相关性(r=0.391,P=0.022),但与IL-1β和IL-6水平均无明显相关性(r=0.032、0.164,P=0.855、0.355)。结论慢性脑低灌注损伤后p75NTR可能与 TNF-α等炎性因子有关,并共同参与了CCH-VCI的发病。
Objective To investigate serum p75 neurotrophin receptor-extracellular domain(p75 NTR-ECD) level in patients with chronic cerebral hypoperfusion-vascular cognitive impairment(CCH-VCI) and its relationship with tumor necrosis factor α(TNF-α), interleukin(IL)-1β and IL-6. Methods The clinical data of patients with CCH-VCI(n=34) were collected from Changhai Hospital, Naval Medical University(Second Military Medical University) from Aug. to Dec. 2018. Enzyme linked immunosorbent assay was applied for detection of serum levels of p75 NTR-ECD, TNF-α, IL-1β and IL-6; and the results were then compared with those of ischemic stroke participants(n=34) and healthy controls(n=36), who were all in the same age range. Spearman correlation analysis was used to analyze the relationship between serum p75 NTR-ECD level and the above-mentioned inflammatory factors in CCH-VCI patients. Results The serum p75 NTR-ECD level in the CCHVCI group was significantly higher than those in the healthy control group and the ischemic stroke group(544.36 [440.88, 628.50] pg/mL vs 276.49 [262.59, 313.87] pg/mL and 366.87 [337.09, 450.43] pg/mL, U=87.500 and 335.500, both P<0.05). The serum levels of TNF-α, IL-1β and IL-6 were 196.02(141.20, 280.35) pg/m L, 68.23(60.79, 91.94) pg/m L and 51.04(40.24, 65.26) pg/mL in the CCH-VCI group, respectively, and 218.67(143.76, 281.28) pg/mL, 76.87(59.10, 99.91) pg/mL and 64.45(43.13, 86.76) pg/mL in the ischemic stroke group, respectively, which were all significantly higher than those in the healthy control group(73.71 [56.94, 79.81] pg/mL, 42.98 [34.52, 51.34] pg/mL and 14.97 [11.76, 21.19] pg/mL, respectively; U=31.000 and 4.000, 106.000 and 132.000, and 48.000 and 13.000; all P<0.05). Serum p75 NTR-ECD level in the CCH-VCI patients was correlated with TNF-α level(r=0.391, P=0.022), but not with IL-1β or IL-6 levels(r=0.032 and 0.164, P=0.855 and 0.355). Conclusion Serum p75 NTR level may be related to inflammatory factors(TNF-α) after chronic cerebral hypoperfusion, and they may jointly participate in the pathogenesis of CCH-VCI.
Objective To investigate serum p75 neurotrophin receptor-extracellular domain(p75 NTR-ECD) level in patients with chronic cerebral hypoperfusion-vascular cognitive impairment(CCH-VCI) and its relationship with tumor necrosis factor α(TNF-α), interleukin(IL)-1β and IL-6. Methods The clinical data of patients with CCH-VCI(n=34) were collected from Changhai Hospital, Naval Medical University(Second Military Medical University) from Aug. to Dec. 2018. Enzyme linked immunosorbent assay was applied for detection of serum levels of p75 NTR-ECD, TNF-α, IL-1β and IL-6; and the results were then compared with those of ischemic stroke participants(n=34) and healthy controls(n=36), who were all in the same age range. Spearman correlation analysis was used to analyze the relationship between serum p75 NTR-ECD level and the above-mentioned inflammatory factors in CCH-VCI patients. Results The serum p75 NTR-ECD level in the CCHVCI group was significantly higher than those in the healthy control group and the ischemic stroke group(544.36 [440.88, 628.50] pg/mL vs 276.49 [262.59, 313.87] pg/mL and 366.87 [337.09, 450.43] pg/mL, U=87.500 and 335.500, both P<0.05). The serum levels of TNF-α, IL-1β and IL-6 were 196.02(141.20, 280.35) pg/m L, 68.23(60.79, 91.94) pg/m L and 51.04(40.24, 65.26) pg/mL in the CCH-VCI group, respectively, and 218.67(143.76, 281.28) pg/mL, 76.87(59.10, 99.91) pg/mL and 64.45(43.13, 86.76) pg/mL in the ischemic stroke group, respectively, which were all significantly higher than those in the healthy control group(73.71 [56.94, 79.81] pg/mL, 42.98 [34.52, 51.34] pg/mL and 14.97 [11.76, 21.19] pg/mL, respectively; U=31.000 and 4.000, 106.000 and 132.000, and 48.000 and 13.000; all P<0.05). Serum p75 NTR-ECD level in the CCH-VCI patients was correlated with TNF-α level(r=0.391, P=0.022), but not with IL-1β or IL-6 levels(r=0.032 and 0.164, P=0.855 and 0.355). Conclusion Serum p75 NTR level may be related to inflammatory factors(TNF-α) after chronic cerebral hypoperfusion, and they may jointly participate in the pathogenesis of CCH-VCI.
引文
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[15]BELKHELFA M,BEDER N,MOUHOUB D,AMRIM,HAYET R,TIGHILT N,et al.The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia[J].J Neuroimmunol,2018,320:48-57.
[16]S A L M I N E N A,H U U S K O N E N J,O J A L A J,KAUPPINEN A,KAARNIRANTA K,SUURONENT.Activation of innate immunity system during aging:NF-κB signaling is the molecular culprit of inflammaging[J].Ageing Res Rev,2008,7:83-105.
[17]IRMADY K,JACKMAN K A,PADOW V A,SHAHANIN,MARTIN L A,CERCHIETTI L,et al.MiR-592regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury[J].J Neurosci,2014,34:3419-3428.
[18]PARK J A,LEE J Y,SATO T A,KOH J Y.Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat[J].J Neurosci,2000,20:9096-9103.
[19]WEI Y,WANG N,LU Q,ZHANG N,ZHENG D,LIJ.Enhanced protein expressions of sortilin and p75NTRin retina of rat following elevated intraocular pressureinduced retinal ischemia[J].Neurosci Lett,2007,429(2/3):169-174.
[20]CHOI S,FRIEDMAN W J.Inflammatory cytokines IL-1βand TNF-αregulate p75NTR expression in CNSneurons and astrocytes by distinct cell-type-specific signalling mechanisms[J/OL].ASN Neuro,2009,1:e00010.doi:10.1042/AN20090009.
[21]CHOI S,FRIEDMAN W J.Interleukin-1βenhances neuronal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75NTR and sortillin[J].Neuroscience,2014,257:11-19.
[2]GORELICK P B.Role of inflammation in cognitive impairment:results of observational epidemiological studies and clinical trials[J].Ann N Y Acad Sci,2010,1207:155-162.
[3]JIAO S S,BU X L,LIU Y H,WANG Q H,LIU CH,YAO X Q,et al.Differential levels of p75NTRectodomain in CSF and blood in patients with Alzheimer’s disease:a novel diagnostic marker[J/OL].Transl Psychiatry,2015,5:e650.doi:10.1038/tp.2015.146.
[4]GORELICK P B,SCUTERI A,BLACK S E,DECARLIC,GREENBERG S M,IADECOLA C,et al;American Heart Association Stroke Council,Councilon Epidemiology and Prevention,Council on Cardiovascular Nursing,Council on Cardiovascular Radiology and Intervention,and Council on Cardiovascular Surgery and Anesthesia.Vascular contributions to cognitive impairment and dementia:a statement for healthcare professionals from the american heart association/american stroke association[J].Stroke,2011,42:2672-2713.
[5]田金洲,解恒革,秦斌,樊东升,时晶,王鲁宁.中国血管性轻度认知损害诊断指南[J].中华内科杂志,2016,55:249-256.
[6]ROMáN G C.Brain hypoperfusion:a critical factor in vascular dementia[J].Neurol Res,2004,26:454-458.
[7]VIJAYAN M,KUMAR S,BHATTI J S,REDDY PH.Molecular links and biomarkers of stroke,vascular dementia,and Alzheimer’s disease[J].Prog Mol Biol Transl Sci,2017,146:95-126.
[8]IADECOLA C.The pathobiology of vascular dementia[J].Neuron,2013,80:844-866.
[9]SCHMIDT R,SCHMIDT H,CURB J D,MASAKI K,WHITE L R,LAUNER L J.Early inflammation and dementia:a 25-year follow-up of the Honolulu-Asia aging study[J].Ann Neurol,2002,52:168-174.
[10]ENGELHART M J,GEERLINGS M I,MEIJER J,KILIAAN A,RUITENBERG A,VAN SWIETEN J C,et al.Inflammatory proteins in plasma and the risk of dementia:the Rotterdam study[J].Arch Neurol,2004,61:668-672.
[11]KARVE I P,TAYLOR J M,CRACK P J.The contribution of astrocytes and microglia to traumatic brain injury[J].Br J Pharmacol,2016,173:692-702.
[12]VENKAT P,CHOPP M,CHEN J.Models and mechanisms of vascular dementia[J].Exp Neurol,2015,272:97-108.
[13]MAGALH?ES C A,FERREIRA C N,LOURES C MG,FRAGA V G,CHAVES A C,OLIVEIRA A C R,et al.Leptin,hsCRP,TNF-αand IL-6 levels from normal aging to dementia:relationship with cognitive and functional status[J].J Clin Neurosci,2018,56:150-155.
[14]FUNG H C,CHEN C M,WU Y R,HSU W C,RO L S,LIN J C,et al.Heat shock protein 70 and tumor necrosis factor alpha in Taiwanese patients with dementia[J],Dement Geriatr Cogn Disord,2005,20:1-7.
[15]BELKHELFA M,BEDER N,MOUHOUB D,AMRIM,HAYET R,TIGHILT N,et al.The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia[J].J Neuroimmunol,2018,320:48-57.
[16]S A L M I N E N A,H U U S K O N E N J,O J A L A J,KAUPPINEN A,KAARNIRANTA K,SUURONENT.Activation of innate immunity system during aging:NF-κB signaling is the molecular culprit of inflammaging[J].Ageing Res Rev,2008,7:83-105.
[17]IRMADY K,JACKMAN K A,PADOW V A,SHAHANIN,MARTIN L A,CERCHIETTI L,et al.MiR-592regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury[J].J Neurosci,2014,34:3419-3428.
[18]PARK J A,LEE J Y,SATO T A,KOH J Y.Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat[J].J Neurosci,2000,20:9096-9103.
[19]WEI Y,WANG N,LU Q,ZHANG N,ZHENG D,LIJ.Enhanced protein expressions of sortilin and p75NTRin retina of rat following elevated intraocular pressureinduced retinal ischemia[J].Neurosci Lett,2007,429(2/3):169-174.
[20]CHOI S,FRIEDMAN W J.Inflammatory cytokines IL-1βand TNF-αregulate p75NTR expression in CNSneurons and astrocytes by distinct cell-type-specific signalling mechanisms[J/OL].ASN Neuro,2009,1:e00010.doi:10.1042/AN20090009.
[21]CHOI S,FRIEDMAN W J.Interleukin-1βenhances neuronal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75NTR and sortillin[J].Neuroscience,2014,257:11-19.