Volume 78, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


To evaluate possible blood-brain barrier (BBB) dysfunction caused by matrix metalloproteinase-9 (MMP-9) and its regulation by tissue inhibitors of metalloproteinase (TIMPs) in patients with eosinophilic meningitis caused by infection with , 40 patients and 28 controls were included in this study. Concentrations of MMP-2, MMP-9, TIMP-1, and cerebrospinal fluid (CSF):serum albumin ratios (Q values) were significantly increased in patients compared with controls. However, concentrations of TIMP-4 were significantly lower in patients. In contrast to MMP-2, proteolytic activity of MMP-9 detected by gelatin zymography was only observed in patients with eosinophilic meningitis. We detected higher levels of antibodies specific for and higher Q values and MMP-9 concentrations in CSF of patients with eosinophilic meningitis, Furthermore, the increase in the Q value was significantly correlated with the increase in MMP-9 in patients. In parallel with CSF MMP-9, patients also showed an increase in CSF leukocyte counts. Gradual decreases in levels of Q, MMP-9, and TIMP-1 and increases in levels of TIMP-4 were observed in six patients during recovery from eosinophilic meningitis. These results suggest that the source of MMP-9 in CSF of patients with eosinophilic meningitis was probably associated with leukocytes migrating from peripheral blood to CSF. Activity of MMP-9 in CSF of patients could not be completely inhibited because of the decrease of TIMP-4, which may cause BBB dysfunction, as shown by higher Q values in patients.


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  1. Beaver PC, Rosen L, 1945. Memorandum on the first report of Angiostrongylus in man by Nomura and Lin. Am J Trop Med Hyg 13 : 589–590. [Google Scholar]
  2. Rosen L, Chappell R, Laqueur GL, 1962. Eosinophilic meningoencephalitis caused by a metastrongylid lung worm of rats. JAMA 179 : 620–624. [Google Scholar]
  3. Punyagupta S, Juttijudata P, Bunnag T, 1975. Eosinophilic meningitis in Thailand: clinical studies of 484 typical cases probably caused by Angiostrongylus. Am J Trop Med Hyg 24 : 921–931. [Google Scholar]
  4. Yii CY, 1976. Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis in Taiwan. Am J Trop Med Hyg 25 : 233–249. [Google Scholar]
  5. Marshall DW, Brey RL, Cahill WT, Houk RW, Zajac RA, Boswell RN, 1988. Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection. Arch Neurol 45 : 954–958. [Google Scholar]
  6. Singer EJ, Syndulko K, Fahy-Chandon B, Schmid P, Conrad A, Tourtellotte WW, 1994. Intrathecal IgG synthesis and albumin leakage are increased in subjects with HIV-1 neurologic disease. J Acquir Immune Defic Syndr 7 : 265–271. [Google Scholar]
  7. Lee JD, Tsai LY, Chen CH, Wang JJ, Hsiao JK, Yen CM, 2006. Blood-brain barrier dysfunction occurring in mice infected with Angiostrongylus cantonensis. Acta Trop 97 : 204–211. [Google Scholar]
  8. Chen KM, Liu JY, Lai SC, Hsu LS, Lee HH, 2006. Association of plasminogen activators and matrix metalloproteinase-9 proteolytic cascade with blood-CNS barrier damage of angiostrongyliasis. Int J Exp Pathol 87 : 113–119. [Google Scholar]
  9. Persidsky Y, Zheng J, Miller D, Gendelman HE, 2000. Mono-nuclear phagocytes mediate blood–brain barrier compromise and neuronal injury during HIV-1-associated dementia. J Leukoc Biol 68 : 413–422. [Google Scholar]
  10. Leppert D, Lindberg RL, Kappos L, Leib SL, 2001. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res Brain Res Rev 36 : 249–257. [Google Scholar]
  11. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G, 2002. Biochemistry and molecular biology of gelatinease B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 37 : 375–536. [Google Scholar]
  12. Latronico T, Liuzzi GM, Riccio P, Lichtner M, Mengoni F, D’Agostino C, Vullo V, Mastroianni CM, 2007. Antiretroviral therapy inhibits matrix metalloproteinase-9 from blood mono-nuclear cells of HIV-infected patients. AIDS 21 : 677–684. [Google Scholar]
  13. Crocker SJ, Pagenstecher A, Campbell IL, 2004. The TIMPs tango with MMPs and more in the central nervous system. J Neurosci Res 75 : 1–11. [Google Scholar]
  14. Amour A, Knight CG, Webster A, Slocombe PM, Stephens PE, Knauper V, Docherty AJ, Murphy G, 2000. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 473 : 275–279. [Google Scholar]
  15. Stetler-Stevenson WG, Brown PD, Onisto M, Levy AT, Liotta LA, 1990. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem 265 : 13933–13938. [Google Scholar]
  16. Blavier L, DeClerck YA, 1997. Tissue inhibitor of metalloproteinases-2 is expressed in the interstitial matrix in adult mouse organs and during embryonic development. Mol Biol Cell 8 : 1513–1527. [Google Scholar]
  17. Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE, 1996. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271 : 30375–30380. [Google Scholar]
  18. Leco KJ, Apte SS, Taniguchi GT, Hawkes SP, Khokha R, Schultz GA, Edwards DR, 1997. Murine tissue inhibitor of metalloproteinases-4 (TIMP-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett 401 : 213–217. [Google Scholar]
  19. Dollery CM, McEwan JR, Wang M, Sang QA, Liu YE, Shi YE, 1999. TIMP-4 is regulated by vascular injury in rats. Circ Res 84 : 498–504. [Google Scholar]
  20. Wang M, Liu YE, Greene J, Sheng S, Fuchs A, Rosen EM, Shi YE, 1997. Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14 : 2767–2774. [Google Scholar]
  21. Liu YE, Wang M, Greene J, Su J, Ullrich S, Li H, Sheng S, Alexander P, Sang QA, Shi YE, 1997. Preparation and characterization of recombination TIMP-4. J Biol Chem 272 : 20479–20483. [Google Scholar]
  22. Chen KM, Lee HH, Chou HL, Liu JY, Tsai BC, Lai SC, 2005. Upregulation of MMP-9/TIMP-1 enzymatic system in eosinophilic meningitis caused by Angiostrongylus cantonensis. Int J Exp Path 86 : 81–89. [Google Scholar]
  23. Tsai HC, Lee SS, Huang CK, Yen CM, Chen ER, Liu YC, 2004. Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 71 : 222–226. [Google Scholar]
  24. Tsai HC, Liu YC, Kunin CM, Lee SS, Chen YS, Lin HH, Tsai TH, Lin WR, Huang CK, Yen MY, Yen CM, 2001. Eosinophilic meningitis caused by Angiostrongylus cantonensis: report of 17 cases. Am J Med 111 : 109–114. [Google Scholar]
  25. Tsai HC, Liu YC, Kunin CM, Lai PH, Lee SS, Chen YS, Wann SR, Lin WR, Huang CK, Ger LP, Lin HH, Yen MY, 2003. Eosinophilic meningitis caused by Angiostrongylus cantonensis associated with eating raw snails: correlation of brain magnetic resonance Imaging scans with clinical findings. Am J Trop Med Hyg 68 : 281–285. [Google Scholar]
  26. Tsai HC, Liu YC, Susan Lee SJ, Chen ER, Yen CM, 2007. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongylus cantoenesis infection. Am J Trop Med Hyg 76 : 592–595. [Google Scholar]
  27. Chye SM, Chang JH, Yen CM, 2000. Immunodiagnosis of human eosinophilic meningitis using an antigen of Angiostrongylus cantonensis L5 with molecular weight 204KD. Acta Trop 75 : 9–17. [Google Scholar]
  28. Petralanda I, Yarzabal L, Piessens WF, 1986. Studies on a filarial antigen with collagenase activity. Mol Biochem Parasitol 19 : 51–59. [Google Scholar]
  29. Robertson BD, Bianco AT, McKerrow JH, Maizels RM, 1989. Toxocara canis: proteolytic enzymes secreted by the infective larvae in vitro. Exp Parasitol 69 : 30–36. [Google Scholar]
  30. McKerrow JH, Brindley P, Brown M, Gam AA, Staunton C, Neva FA, 1990. Strongyloides stercoralis: identification of a protease that facilitates penetration of skin by the infective larvae. Exp Parasitol 70 : 134–143. [Google Scholar]
  31. Healer J, Ashall F, Maizels RM, 1991. Characterization of proteolytic enzymes from larval and adult Nippostrongylus brasiliensis. Parasitology 103 : 305–314. [Google Scholar]
  32. Richer JK, Sakanari JA, Frank GR, Grieve RB, 1992. Dirofilaria immitis: proteases produced by third- and fourth-stage larvae. Exp Parasitol 75 : 213–222. [Google Scholar]
  33. Hill DE, Gamble HR, Rhoads ML, Fetterer RH, Urban JF Jr, 1993. Trichuris suis: a zinc metalloprotease from culture fluids of adult parasites. Exp Parasitol 77 : 170–178. [Google Scholar]
  34. Hawdon JM, Jones BF, Perregaux MA, Hotez PJ, 1995. Ancylostoma caninum: metalloprotease release coincides with activation of infective larvae in vitro. Exp Parasitol 80 : 205–211. [Google Scholar]
  35. Wada K, Sato H, Kinoh H, Kajita M, Yamamoto H, Seiki M, 1998. Cloning of three Caenorhabditis elegans genes potentially encoding novel matrix metalloproteinases. Gene 211 : 57–62. [Google Scholar]
  36. Uparanukraw P, Morakote N, Harnnoi T, Dantrakool A, 2001. Molecular cloning of a gene encoding matrix metalloproteinase-like protein from Gnathostoma spinigerum. Parasitol Res 87 : 751–757. [Google Scholar]
  37. Lai SC, Jiang ST, Chen KM, Lee HH, 2005. Matrix metalloproteinases activity demonstrated in the infective stage of the nematodes, Angiostrongylus cantonensis. Parasitol Res 97 : 466–471. [Google Scholar]
  38. Gijbels K, Masure S, Carton H, Opdenakker G, 1992. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J Neuroimmunol 41 : 29–34. [Google Scholar]
  39. Paemen L, Olsson T, Söderström M, Van Damme J, Opdenakker G, 1994. Evaluation of gelatinases and IL-6 in the cerebrospinal fluid of patients with optic neuritis, multiple sclerosis and other inflammatory neurological diseases. Eur J Neurol 1 : 55–63. [Google Scholar]
  40. Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S, Miller KM, Hauser SL, Kappos L, 1998. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121 : 2327–2334. [Google Scholar]
  41. Sporer B, Paul R, Koedel U, Grimm R, Wick M, Goebel FD, Pfister HW, 1998. Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients. J Infect Dis 178 : 854–857. [Google Scholar]
  42. Perides G, Charness ME, Tanner LM, Peter O, Satz N, Steere AC, Klempner MS, 1998. Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis. J Infect Dis 177 : 401–408. [Google Scholar]
  43. Kolb SA, Lahrtz F, Paul R, Leppert D, Nadal D, Pfister HW, Fontana A, 1998. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid. J Neuroimmunol 84 : 143–150. [Google Scholar]
  44. Mustafa MM, Ramilo O, Mertsola J, Risser RC, Beutler B, Hansen EJ, McCracker GH, 1989. Modulation of inflammation and cachectin activity in relation to treatment of experimental Haemophilus influenzae type b meningitis. J Infect Dis 160 : 818–825. [Google Scholar]
  45. Rosenberg GA, Dencoff JE, Correa N Jr, Reiners M, Ford CC, 1996. Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology 46 : 1626–1632. [Google Scholar]
  46. Chotmongkol V, Sawanyawisuth K, Thavornpitak Y, 2000. Corticosteroid treatment of eosinophilic meningitis. Clin Infect Dis 31 : 660–662. [Google Scholar]
  47. Sawanyawisuth K, Limpawattana P, Busaracome P, Ninpaitoon B, Chotmongkol V, Intapan PM, Tanawirattananit S, 2004. 1-week course of corticosteroids in the treatment of eosinophilic meningitis. Am J Med 117 : 802–803. [Google Scholar]
  48. Welgus HG, Campbell EJ, Curry JD, Eisen AZ, Senior RM, Wilhelm SM, Goldberg GI, 1990. Neutral metalloproteinases produced by human mononuclear phagocytes. J Clin Invest 86 : 1496–1502. [Google Scholar]
  49. Foerster C, Kahles T, Kietz S, Drenckhahn D, 2007. Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND. J Physiol 580 : 937–949. [Google Scholar]
  50. Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG, 1992. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res 576 : 203–207. [Google Scholar]
  51. Kieseier BC, Paul R, Koedel U, Seifert T, Clements JM, Gearing AJ, Pfister HW, Hartung HP, 1999. Differential expression of matrix metalloproteinases in bacterial meningitis. Brain 122 : 1579–1587. [Google Scholar]
  52. Matsuura E, Umehara F, Hashiguchi T, Fujimoto N, Okada Y, Osame M, 2000. Marked increase of matrix metalloproteinase 9 in cerebrospinal fluid of patients with fungal or tuberculous meningoencephalitis. J Neurol Sci 173 : 45–52. [Google Scholar]
  53. Azeh I, Mader M, Smirnov A, Beuche W, Nau R, Weber F, 1998. Experimental pneumococcal meningitis in rabbits: the increase of matrix metalloproteinase-9 in cerebrospinal fluid correlates with leucocyte invasion. Neurosci Lett 256 : 127–130. [Google Scholar]
  54. Lee KY, Kim EH, Yang WS, Ryu H, Cho SN, Lee BI, Heo JH, 2004. Persistent increase of matrix metalloproteinases in cerebrospinal fluid of tuberculous meningitis. J Neurol Sci 220 : 73–78. [Google Scholar]
  55. Cheung C, Luo H, Yanagawa B, Leong HS, Samarasekera D, Lai JC, Suarez A, Zhang J, McManus BM, 2006. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis. Cardiovasc Pathol 15 : 63–74. [Google Scholar]
  56. Bode W, Fernandez-Catalan C, Grams F, Gomis-Ruth FX, Nagase H, Tschesche H, Maskos K, 1999. Insights into MMP-TIMP interactions. Ann N Y Acad Sci 878 : 73–91. [Google Scholar]

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  • Received : 28 Jun 2007
  • Accepted : 15 Oct 2007

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