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Association of Matrix Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinase-4 in Cerebrospinal Fluid with Blood-Brain Barrier Dysfunction in Patients with Eosinophilic Meningitis Caused by Angiostrongylus cantonensis

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 Angiostrongylus cantonensis, 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_Alb 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 A. cantonensis and higher Q_Alb values and MMP-9 concentrations in CSF of patients with eosinophilic meningitis, Furthermore, the increase in the Q_Alb 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_Alb, 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_Alb values in patients.

Received June 28, 2007. Accepted for publication October 15, 2007.

Acknowledgments: We thank Min-Hon Shi for assistance with zymography.

Financial support: This work is supported by grant VGHKS96-027 from Kaohsiung Veterans General Hospital, and grant NSC-96-2320-B-075B-002 from the National Science Council, Republic of China.

^* Address correspondence to Chuan-Min Yen, Department of Parasitology, Kaohsiung Medical University, #100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan, Republic of China. E-mail: hctsai1011 @yahoo.com.tw

Authors’ addresses: Hung-Chin Tsai, Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital 386, Ta-Chung 1st Road, Kaohsiung City, 813, Taiwan, Republic of China, National Yang-Ming University, Taipei, Taiwan, Republic of China, and Department of Parasitology and Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan, Republic of China. Eng-Rin Chen, Li-Yu Chung, and Chuan-Min Yen, Department of Parasitology and Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan, Republic of China. Yung-Ching Liu, Susan Shin-Jung Lee, Yao-Shen Chen, Cheng-Len Sy, and Shue-Ren Wann, Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital 386, Ta-Chung 1st Road, Kaohsiung City, 813, Taiwan and National Yang-Ming University, Taipei, Taiwan, Republic of China.