VEGF及TGF-β1在结核性脑膜炎患者发病机制中的探讨
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摘要
目的:结核性脑膜炎(tuberculous meningitis, TBM)是结核杆菌侵入蛛网膜下腔所引起的脑膜结核性炎症改变,病变除累及软脑膜外,蛛网膜、脑实质、脑血管也常常受累,是常见最严重的肺外结核病。结核病发生、发展和转归不仅与感染的细菌量及其毒力等因素有关,且取决于机体免疫功能。颅内感染时,炎性细胞或血小板等均可产生血管内皮生长因子(vascular endothelial growth factor,VEGF),破坏血脑屏障,加重脑水肿。转化生长因子β1(transforming growth factorβ1,TGF-β1) ,是抑制T细胞、单核巨噬细胞功能的一个细胞因子,它可能参与结核病免疫发病的一个中心环节。本研究旨在通过测定结脑患者脑脊液中VEGF及TGF-β1含量,探讨两者在结核性脑膜炎患者发病机制中的作用,并为今后的免疫、抗炎治疗提供一定的依据。
方法:2008年3月～2009年8月河北医科大学第二医院收治的患者,结脑组:诊断为结核性脑膜炎的患者26例,其中很可能的结核性脑膜炎患者13例,可能的结核性脑膜炎患者6例,可疑的结核性脑膜炎患者7例。对照组:共26例,其中脊肌萎缩症1例,神经症1例,有机磷中毒1例,脊髓蛛网膜炎2例,右肾脓肿1例,脱髓鞘疾病4例,周围神经病1例,多系统萎缩1例,海绵窦综合征1例,门诊腰穿排除中枢神经系统感染患者13例。
入院后对所有病例进行腰穿送检脑脊液常规、生化、细胞学系列检查(MGG染色、阿利新兰染色),应用双抗体夹心ABC-ELISA法测定脑脊液VEGF及TGF-β1含量。
结果:
1脑脊液生化:结脑组蛋白平均值为1.47±0.57g /L,对照组蛋白平均值0.35±0.22g/L,经比较两组差异有统计学意义。结脑组糖平均值为2.07±0.99mmol/L,对照组糖平均值为3.86±1.19mmol /L,经比较两组差异有统计学意义。结脑组氯化物平均值为110.52±8.96mmol/L,对照组氯化物平均值为125.97±6.24mmol/L,经比较两组差异有统计学意义。
2脑脊液VEGF含量测定:结核性脑膜炎组脑脊液中VEGF水平为(15.625～347.457)pg/ml,对照组VEGF水平为(15.625～35.799) pg/ml ,二者比较差异有统计学意义。很可能组脑脊液中VEGF水平为(18.136～347.457)pg/ml,可能及可疑组脑脊液中VEGF水平为(15.625～45.491) pg/ml。很可能组与可能及可疑组比较差异有统计学意义。10例患者治疗前脑脊液中VEGF水平为(15.625～182.407)pg/ml,治疗后脑脊液中VEGF水平为(15.625～22.600) pg/ ml。前后比较差异有统计学意义。Ⅰ级、Ⅱ级、Ⅲ级三组患者之间脑脊液中VEGF水平比较差异均无统计学意义。脑脊液细胞学以嗜中性粒细胞反应为主与淋巴细胞反应为主两组VEGF水平比较差异均无统计学意义。
3脑脊液TGF-β1含量测定:结脑组含量平均值为40.77±8.71pg/ml,对照组含量平均值为37.69±5.05pg/ml,经比较两组差异无统计学意义。
结论:
1结核性脑膜炎患者脑脊液中VEGF水平升高,VEGF蛋白检测可以支持结核性脑膜炎的诊断,动态观察其含量变化对结脑患者的病情监测具有重要意义。
2结核性脑膜炎患者脑脊液中TGF-β1水平虽然高于对照组,但无统计学意义,TGF-β1在结核性脑膜炎发病机制中的作用有待进一步研究。
Objective: Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis,the bacterial invasive subarachnoid and create inflammatory changes involving the leptomeningeal. In addition,the arachnoid,brain parenchyma and cerebral blood vessels are often involved. It is the most serious extrapulmonary tuberculosis.The occurrence,development and fate of tuberculosis are not only depend on the amount and virulence of the bacterial,but also depend on the immune function. In intracranial infection, inflammatory cells or platelet can generate vascular endothelial growth factor (VEGF), which break blood-brain barrier and cause cerebral edema. Transforming growth factor-β1 (TGF-β1) is a cytokine, that can inhibit the function of T cell, monocyte-macrophage cells, it may be involved in the immune pathogenesis of tuberculosis as a central role. In this study, by measuring the levels of vascular endothelial growth factor and Transforming growth factor-β1 in cerebrospinal fluid and observing the dynamic content,in order to explore the pathogenesis of tuberculous meningitis and provide the basis for immunotherapy and anti-inflammatory treatment in the future.
Methods: All these patients were from the Second Hospital of Hebei Medical University during the period of 2008 March~2009 August.
1 tuberculous meningitis: 26 cases are diagnosed as tuberculous meningitis, including 13 of highly probable tuberculous meningitis,6 of probable tuberculous meningitis and 7 of possible tuberculous meningitis.
2 The control group: 1 patient with spinal muscular atrophy,1 patient with neurosis,1 patient with Organophosphate poisoning,2 patients with arachnoiditis of spinal cord,1 patient with renal abscess,4 patients with demyelinating disease,1 patient with peripheral neuropathy,1 patient with multiple system atrophy,1 patient with cavernous sinus syndrome,13 cases of outpatients are excluded central nervous system infection by lumbar puncture.
CSF was collected by lumbar puncture in all patients and were analyzed routine,biochemical and cytology (MGG dye and aricine blue staining). Apply the ABC-ELISA method to measure the level of TGF-β1 and VEGF.
Results:
1 CSF biochemical test:Compare the protein levels in cerebrospinal fluid in tuberculous meningitis (1.47±0.57g/L) and control group(0.35±0.22g /L),there was a statistical significance. Compare the glucose levels in cerebrospinal fluid in tuberculous meningitis (2.07±0.99mmol/L)and control group(3.86±1.19mmol/L),there was a statistical significance. Compare the chloride levels in cerebrospinal fluid in tuberculous meningitis (110.52±8.96 mmol/L) and control group(125.97±6.24mmol/L),there was a statistical significance.
2 The levels of vascular endothelial growth factor in CSF:Compare the vascular endothelial growth factor levels in cerebrospinal fluid in tuberculous meningitis (15.625～347.457) pg/ml and control group(15.625～35.799) pg/ ml,there was a statistical significance. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in highly probable tuberculous meningitis (18.136～347.457) pg/ml and probable combine with possible tuberculous meningitis (15.625～45.491) pg/ ml,there was a statistical significance. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in 10 cases before treatment (15.625～182.407) pg/ml and after treatment (15.625～22.600) pg/ml,there was a statistical significance. It didn’t have significant difference in levelⅠ,ⅡandⅢcases. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in neutrophil cell dominant response and in lymphoid cells dominant response, there was not a statistical significance.
3 The levels of Transforming growth factor-β1 in CSF:Compare the Transforming growth factor-β1 levels in cerebrospinal fluid in tuberculous meningitis (40.77±8.71pg/ml) and control group(37.69±5.05pg/ml), it didn’t have significant difference.
Conclusions:
1 The level of VEGF in cerebrospinal fluid is rised in tuberculous meningitis. Detection of VEGF protein can support the diagnosis of tuberculous meningitis.Through dynamic observing the changes has the significance of disease monitoring in patients with tuberculous meningitis.
2 The level of TGF-β1 in cerebrospinal fluid is higher in tuberculous meningitis than control group,but it didn’t have significant difference. The role of TGF-β1 in the pathogenesis of tuberculous meningitis should be further researched.
方法:2008年3月～2009年8月河北医科大学第二医院收治的患者,结脑组:诊断为结核性脑膜炎的患者26例,其中很可能的结核性脑膜炎患者13例,可能的结核性脑膜炎患者6例,可疑的结核性脑膜炎患者7例。对照组:共26例,其中脊肌萎缩症1例,神经症1例,有机磷中毒1例,脊髓蛛网膜炎2例,右肾脓肿1例,脱髓鞘疾病4例,周围神经病1例,多系统萎缩1例,海绵窦综合征1例,门诊腰穿排除中枢神经系统感染患者13例。
入院后对所有病例进行腰穿送检脑脊液常规、生化、细胞学系列检查(MGG染色、阿利新兰染色),应用双抗体夹心ABC-ELISA法测定脑脊液VEGF及TGF-β1含量。
结果:
1脑脊液生化:结脑组蛋白平均值为1.47±0.57g /L,对照组蛋白平均值0.35±0.22g/L,经比较两组差异有统计学意义。结脑组糖平均值为2.07±0.99mmol/L,对照组糖平均值为3.86±1.19mmol /L,经比较两组差异有统计学意义。结脑组氯化物平均值为110.52±8.96mmol/L,对照组氯化物平均值为125.97±6.24mmol/L,经比较两组差异有统计学意义。
2脑脊液VEGF含量测定:结核性脑膜炎组脑脊液中VEGF水平为(15.625～347.457)pg/ml,对照组VEGF水平为(15.625～35.799) pg/ml ,二者比较差异有统计学意义。很可能组脑脊液中VEGF水平为(18.136～347.457)pg/ml,可能及可疑组脑脊液中VEGF水平为(15.625～45.491) pg/ml。很可能组与可能及可疑组比较差异有统计学意义。10例患者治疗前脑脊液中VEGF水平为(15.625～182.407)pg/ml,治疗后脑脊液中VEGF水平为(15.625～22.600) pg/ ml。前后比较差异有统计学意义。Ⅰ级、Ⅱ级、Ⅲ级三组患者之间脑脊液中VEGF水平比较差异均无统计学意义。脑脊液细胞学以嗜中性粒细胞反应为主与淋巴细胞反应为主两组VEGF水平比较差异均无统计学意义。
3脑脊液TGF-β1含量测定:结脑组含量平均值为40.77±8.71pg/ml,对照组含量平均值为37.69±5.05pg/ml,经比较两组差异无统计学意义。
结论:
1结核性脑膜炎患者脑脊液中VEGF水平升高,VEGF蛋白检测可以支持结核性脑膜炎的诊断,动态观察其含量变化对结脑患者的病情监测具有重要意义。
2结核性脑膜炎患者脑脊液中TGF-β1水平虽然高于对照组,但无统计学意义,TGF-β1在结核性脑膜炎发病机制中的作用有待进一步研究。
Objective: Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis,the bacterial invasive subarachnoid and create inflammatory changes involving the leptomeningeal. In addition,the arachnoid,brain parenchyma and cerebral blood vessels are often involved. It is the most serious extrapulmonary tuberculosis.The occurrence,development and fate of tuberculosis are not only depend on the amount and virulence of the bacterial,but also depend on the immune function. In intracranial infection, inflammatory cells or platelet can generate vascular endothelial growth factor (VEGF), which break blood-brain barrier and cause cerebral edema. Transforming growth factor-β1 (TGF-β1) is a cytokine, that can inhibit the function of T cell, monocyte-macrophage cells, it may be involved in the immune pathogenesis of tuberculosis as a central role. In this study, by measuring the levels of vascular endothelial growth factor and Transforming growth factor-β1 in cerebrospinal fluid and observing the dynamic content,in order to explore the pathogenesis of tuberculous meningitis and provide the basis for immunotherapy and anti-inflammatory treatment in the future.
Methods: All these patients were from the Second Hospital of Hebei Medical University during the period of 2008 March~2009 August.
1 tuberculous meningitis: 26 cases are diagnosed as tuberculous meningitis, including 13 of highly probable tuberculous meningitis,6 of probable tuberculous meningitis and 7 of possible tuberculous meningitis.
2 The control group: 1 patient with spinal muscular atrophy,1 patient with neurosis,1 patient with Organophosphate poisoning,2 patients with arachnoiditis of spinal cord,1 patient with renal abscess,4 patients with demyelinating disease,1 patient with peripheral neuropathy,1 patient with multiple system atrophy,1 patient with cavernous sinus syndrome,13 cases of outpatients are excluded central nervous system infection by lumbar puncture.
CSF was collected by lumbar puncture in all patients and were analyzed routine,biochemical and cytology (MGG dye and aricine blue staining). Apply the ABC-ELISA method to measure the level of TGF-β1 and VEGF.
Results:
1 CSF biochemical test:Compare the protein levels in cerebrospinal fluid in tuberculous meningitis (1.47±0.57g/L) and control group(0.35±0.22g /L),there was a statistical significance. Compare the glucose levels in cerebrospinal fluid in tuberculous meningitis (2.07±0.99mmol/L)and control group(3.86±1.19mmol/L),there was a statistical significance. Compare the chloride levels in cerebrospinal fluid in tuberculous meningitis (110.52±8.96 mmol/L) and control group(125.97±6.24mmol/L),there was a statistical significance.
2 The levels of vascular endothelial growth factor in CSF:Compare the vascular endothelial growth factor levels in cerebrospinal fluid in tuberculous meningitis (15.625～347.457) pg/ml and control group(15.625～35.799) pg/ ml,there was a statistical significance. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in highly probable tuberculous meningitis (18.136～347.457) pg/ml and probable combine with possible tuberculous meningitis (15.625～45.491) pg/ ml,there was a statistical significance. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in 10 cases before treatment (15.625～182.407) pg/ml and after treatment (15.625～22.600) pg/ml,there was a statistical significance. It didn’t have significant difference in levelⅠ,ⅡandⅢcases. Compare the vascular endothelial growth factor levels in cerebrospinal fluid in neutrophil cell dominant response and in lymphoid cells dominant response, there was not a statistical significance.
3 The levels of Transforming growth factor-β1 in CSF:Compare the Transforming growth factor-β1 levels in cerebrospinal fluid in tuberculous meningitis (40.77±8.71pg/ml) and control group(37.69±5.05pg/ml), it didn’t have significant difference.
Conclusions:
1 The level of VEGF in cerebrospinal fluid is rised in tuberculous meningitis. Detection of VEGF protein can support the diagnosis of tuberculous meningitis.Through dynamic observing the changes has the significance of disease monitoring in patients with tuberculous meningitis.
2 The level of TGF-β1 in cerebrospinal fluid is higher in tuberculous meningitis than control group,but it didn’t have significant difference. The role of TGF-β1 in the pathogenesis of tuberculous meningitis should be further researched.
引文
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1 Ichiyama T, Hayashi T, Nishikawa M, et al.Levels of Transforming Growth Factor b1, Tumor Necrosis Factor a, and Interleukin 6 in Cerebrospinal Fluid: Association with Clinical Outcome for Children with Bacterial Meningitis. Clin Infect Dis, 1997,25(2):328-329
2 Huang CC, Chang YC, Chow NH, et al.Level of transforming growth factor beta 1 is elevated in cerebrospinal fluid of children with acute bacterial meningitis.J Neurol,1997,244(10):634-638
3 Malipiero U, Koedel U, Pfister H-W, et al. TGFbeta receptor II genedeletion in leukocytes prevents cerebral vasculitis in bacterial meningitis. Brain ,2006, 129: 2404–2415
4 Malipiero U, Koedel U, Pfister W, et al. Bacterial Meningitis: The Role of Transforming Growth Factor-Beta in Innate Immunity and Secondary Brain Damage. Neurodegener Dis,2007,4(1):43-50
5 Ossege LM, Sindern E, Voss B, et al.Expression of tumor necrosis factor-a and transforming growth factorβ1 in cerebrospinal fluid cells in meningitis. J Neurol Sci,1996,144(1-2):1-13
6 Brown H, Turner G, Rogerson S, et al. Cytokine Expression in the Brain in Human Cerebral Malaria. J Infect Dis,1999,180(5):1742-1746
7 Deininger MH, Kremsner PG, Meyermann R, et al. Differential Cellular Accumulation of Transforming Growth Factor–b1,–b2, and–b3 in Brains of Patients Who Died with Cerebral Malaria. J Infect Dis,2000, 181(6):2111-2115
8 Armah H, Wired EK, Dodoo AK, et al .Cytokines and Adhesion Molecules Expression in the Brain in Human Cerebral Malaria. Int J Environ Res Public Health,2005,2(1):123-131
9 Sato M, Hosoya M, Honzumi K, et al. Cytokine and Cellular Inflammatory Sequence in Enteroviral Meningitis. Pediatrics, 2003 ,112(5):1103-1107
10 Navikas V, Haglund M, Link J, et al. Cytokine mRNA Profiles in Mononuclear Cells in Acute Aseptic Meningoencephalitis. Infect Immun, 1995,63(4):1581-1586
11 Johnson MD, Gold LI. Distribution of Transforming Growth Factor-Isoforms in Human Immunodeficiency Virus-I Encephalitis. Hum Pathol,1996,27(7):643-649
12 Narita M, Tanaka H, Togashi T, et al. Cytokines Involved in CNS Manifestations Caused by Mycoplasma pneumoniae. Pediatr Neurol,2005, 33(2):105-109
13 Maffei CM, Mirels LF, Sobel RA, et al. Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis. Infect Immun,2004,72(4):2338-2349
14邹华芳,赵玲玲血管内皮细胞生长因子与颅内感染的关系.国外医学神经病学神经外科学分册,2004,31(3):254-257
15 Matsuyama W, Hashiguchi T, Umehara F, et al. Expression of vascular endothelial growth factor in tuberculous meningitis. J Neurol Sci,2001,186(1-2):75-79
16 van der Flier M, Hoppenreijs S, van Rensburg AJ, et al. Vascular Endothelial Growth Factor and Blood-Brain Barrier Disruption in Tuberculous Meningitis. Pediatr Infect Dis J, 2004,23(7):608-613
17 Husain N, Awasthi S, Haris M, et al. Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis. J Infect, 2008, 56(2):114-119
18 van der Flier M, Stockhammer G, Vonk GJ, et al. Vascular Endothelial Growth Factor in Bacterial Meningitis: Detection in Cerebrospinal Fluid and Localization in Postmortem Brain.J Infect Dis, 2001,183(1):149-153
19赵玲玲,邹华芳,高喜容脑脊液VEGF蛋白检测在新生儿细菌性脑膜炎的临床意义.实用预防医学,2006,13(5):1126-1128
20孙桂莲,李萍.急性病毒性脑炎患儿血清中VEGF和IL-6水平的研究.中国医科大学学报,2004,33(5):456-457
21杨风华,王华,张俊梅等病毒性脑炎患儿脑脊液中VEGF VCAM-1变化及其意义.中国当代儿科杂志, 2008,10(3):285-289
22 Coenjaerts FE, van der Flier M, Mwinzi PN, et al. Intrathecal Production and Secretion of Vascular Endothelial Growth Factor during Cryptococcal Meningitis. J Infect Dis, 2004 ,190(7):1310-1317
23 Hoepelman AI, Van der Flier M, Coenjaerts FE. Dexamethasone downregulates Cryptococcus neoformans-induced vascular endothelial growth factor production: a role for corticosteroids in cryptococcal meningitis? J Acquir Immune Defic Syndr,2004,37(3):1431-1432
24 Sporer B, Koedel U, Paul R, et al. Vascular endothelial growth factor (VEGF) is increased in serum, but not in cerebrospinal fluid in HIV associated CNS diseases. J Neurol Neurosurg Psychiatry,2004, 75(2): 298-300
25 Tsai HC,Liu YC,Lee SS. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongylus cantonensis infection. Am J Trop Med Hyg, 2007, 76(3):592-595
26 Nauck M,Karakiulakis G,Papakonstantinou E,et al. Corticosteroids inhibit the expression of the vascular endothelial growth factor in human vascular smooth muscle cells.Eur J Pharmacol,1998,341(2-3):309-315
2邹华芳,赵玲玲.血管内皮细胞生长因子与颅内感染的关系.国外医学神经病学神经外科学分册,2004,31(3):254-257
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5 G.K.Ahuja,K.K.Mohan,K.Prasad,et al. Diagnostic criteria for tuberculous meningitis and their validation Tuber Lung Dis,1994,75(2):149-152
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8冯玉麟,刘立荣,张尚福,等.结核性脑膜炎129例的临床与病理.中华结核和呼吸杂志,1997, 20(3):161-163
9韩雄,李森,索爱琴.脑脊液生化异常与结核性脑膜炎患者病情的关系.中国临床神经科学,2004,12(4):381-384.
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23 Matsuyama W, Kubota R, Hashiguchi T, et al. Purified protein derivative of tuberculin upregulates the expression of vascular endothelial growth factor in T lymphocytes in vitro. Immunology,2002,106(1):96-101
24 Kiropoulos TS, Kostikas K, Gourgoulianis KI, et al.Vascular Endothelial Growth Factor Levels in Pleural Fluid and Serum of Patients With Tuberculous Pleural Effusions. Chest,2005,128(1):468
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27 Husain N, Awasthi S, Haris M, et al. Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis. J Infect, 2008, 56(2): 114-119
28 Fischer S, Renz D, Schaper W, et al. In vitro effects of dexamethasone on hypoxia-induced hyperpermeability and expression of vascular endothelial growth factor. Eur J Pharmacol, 2001,411(3): 231-243
29 Nauck M, Karakiulakis G, Papakonstantinou E, et al. Corticosteroids inhibit the expression of the vascular endothelial growth factor in human vascular smooth muscle cells. Eur J Pharmacol, 1998,341(2-3):309-315
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32 van der Flier M, Stockhammer G, Vonk GJ, et al. Vascular Endothelial Growth Factor in Bacterial Meningitis: Detection in Cerebrospinal Fluid and Localization in Postmortem Brain. J Infect Dis,2001,183(1):149-153
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53 Bakhiet M, Mustafa M, Zhu J.Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis.Clin Exp Immunol, 1998, 114(3): 398-402
1 Ichiyama T, Hayashi T, Nishikawa M, et al.Levels of Transforming Growth Factor b1, Tumor Necrosis Factor a, and Interleukin 6 in Cerebrospinal Fluid: Association with Clinical Outcome for Children with Bacterial Meningitis. Clin Infect Dis, 1997,25(2):328-329
2 Huang CC, Chang YC, Chow NH, et al.Level of transforming growth factor beta 1 is elevated in cerebrospinal fluid of children with acute bacterial meningitis.J Neurol,1997,244(10):634-638
3 Malipiero U, Koedel U, Pfister H-W, et al. TGFbeta receptor II genedeletion in leukocytes prevents cerebral vasculitis in bacterial meningitis. Brain ,2006, 129: 2404–2415
4 Malipiero U, Koedel U, Pfister W, et al. Bacterial Meningitis: The Role of Transforming Growth Factor-Beta in Innate Immunity and Secondary Brain Damage. Neurodegener Dis,2007,4(1):43-50
5 Ossege LM, Sindern E, Voss B, et al.Expression of tumor necrosis factor-a and transforming growth factorβ1 in cerebrospinal fluid cells in meningitis. J Neurol Sci,1996,144(1-2):1-13
6 Brown H, Turner G, Rogerson S, et al. Cytokine Expression in the Brain in Human Cerebral Malaria. J Infect Dis,1999,180(5):1742-1746
7 Deininger MH, Kremsner PG, Meyermann R, et al. Differential Cellular Accumulation of Transforming Growth Factor–b1,–b2, and–b3 in Brains of Patients Who Died with Cerebral Malaria. J Infect Dis,2000, 181(6):2111-2115
8 Armah H, Wired EK, Dodoo AK, et al .Cytokines and Adhesion Molecules Expression in the Brain in Human Cerebral Malaria. Int J Environ Res Public Health,2005,2(1):123-131
9 Sato M, Hosoya M, Honzumi K, et al. Cytokine and Cellular Inflammatory Sequence in Enteroviral Meningitis. Pediatrics, 2003 ,112(5):1103-1107
10 Navikas V, Haglund M, Link J, et al. Cytokine mRNA Profiles in Mononuclear Cells in Acute Aseptic Meningoencephalitis. Infect Immun, 1995,63(4):1581-1586
11 Johnson MD, Gold LI. Distribution of Transforming Growth Factor-Isoforms in Human Immunodeficiency Virus-I Encephalitis. Hum Pathol,1996,27(7):643-649
12 Narita M, Tanaka H, Togashi T, et al. Cytokines Involved in CNS Manifestations Caused by Mycoplasma pneumoniae. Pediatr Neurol,2005, 33(2):105-109
13 Maffei CM, Mirels LF, Sobel RA, et al. Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis. Infect Immun,2004,72(4):2338-2349
14邹华芳,赵玲玲血管内皮细胞生长因子与颅内感染的关系.国外医学神经病学神经外科学分册,2004,31(3):254-257
15 Matsuyama W, Hashiguchi T, Umehara F, et al. Expression of vascular endothelial growth factor in tuberculous meningitis. J Neurol Sci,2001,186(1-2):75-79
16 van der Flier M, Hoppenreijs S, van Rensburg AJ, et al. Vascular Endothelial Growth Factor and Blood-Brain Barrier Disruption in Tuberculous Meningitis. Pediatr Infect Dis J, 2004,23(7):608-613
17 Husain N, Awasthi S, Haris M, et al. Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis. J Infect, 2008, 56(2):114-119
18 van der Flier M, Stockhammer G, Vonk GJ, et al. Vascular Endothelial Growth Factor in Bacterial Meningitis: Detection in Cerebrospinal Fluid and Localization in Postmortem Brain.J Infect Dis, 2001,183(1):149-153
19赵玲玲,邹华芳,高喜容脑脊液VEGF蛋白检测在新生儿细菌性脑膜炎的临床意义.实用预防医学,2006,13(5):1126-1128
20孙桂莲,李萍.急性病毒性脑炎患儿血清中VEGF和IL-6水平的研究.中国医科大学学报,2004,33(5):456-457
21杨风华,王华,张俊梅等病毒性脑炎患儿脑脊液中VEGF VCAM-1变化及其意义.中国当代儿科杂志, 2008,10(3):285-289
22 Coenjaerts FE, van der Flier M, Mwinzi PN, et al. Intrathecal Production and Secretion of Vascular Endothelial Growth Factor during Cryptococcal Meningitis. J Infect Dis, 2004 ,190(7):1310-1317
23 Hoepelman AI, Van der Flier M, Coenjaerts FE. Dexamethasone downregulates Cryptococcus neoformans-induced vascular endothelial growth factor production: a role for corticosteroids in cryptococcal meningitis? J Acquir Immune Defic Syndr,2004,37(3):1431-1432
24 Sporer B, Koedel U, Paul R, et al. Vascular endothelial growth factor (VEGF) is increased in serum, but not in cerebrospinal fluid in HIV associated CNS diseases. J Neurol Neurosurg Psychiatry,2004, 75(2): 298-300
25 Tsai HC,Liu YC,Lee SS. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongylus cantonensis infection. Am J Trop Med Hyg, 2007, 76(3):592-595
26 Nauck M,Karakiulakis G,Papakonstantinou E,et al. Corticosteroids inhibit the expression of the vascular endothelial growth factor in human vascular smooth muscle cells.Eur J Pharmacol,1998,341(2-3):309-315