Objectives: Cyclosporin A(CsA) is the immunosuppressor most frequently used in transplant surgery, but one of the adverse side effects by CsA is gingival overgrowth. The previous reports have demonstrated that gingival overgrowth was effectively treated by azithromycin(AZI), a macrolide antibiotic of azalide subclass that suppresses protein synthesis by gram-positive and gram-negative aerobes. However, the mechanism by which AZI suppresses CsA-induced gingival overgrowth(CIGO) has not as yet been elucidated. In the present study, we examined the inhibitory effect of AZI on CIGO and its mechanism of action as well as the mechanism whereby CsA induces GO. Methods: Human gingival fibroblast cells were isolated from the gingival tissues of the healthy subjects and the patients exhibiting GO caused by CsA therapy. Cell proliferation was measured by MTT assay, and mRNA levels and activities of matrix metalloproteinases(MMP) by reverse transcriptase-polymerase chain reaction and zymography, respectively. Results: The CsA treatment resulted in higher proliferation in cells derived from the patient with GO induced by CsA in comparison with those from the healthy subjects. Azithromycin inhibited the cell proliferation of gingival fibroblasts increased by CsA exposure for 5 days. The morphological changes were observed in the gingival cells stimulated with CsA, AZI, and the combination of CsA and AZI. CsA inhibited the mRNA level and activity of MMP-2, but those of MMP-9 were not detected in the cells treated with CsA. In contrast, the latent and active form of MMP-2 and -9 were induced by AZI. Conclusions: The induction of MMP-2 and ? by AZI treatment plays an important role for the inhibition of AZI on CIGO. This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ5-PG3-20507-0020).

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