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. 2017 Nov 18;10(11):1647-1654.
doi: 10.18240/ijo.2017.11.03. eCollection 2017.

Effect of itraconazole on the cornea in a murine suture model and penetrating keratoplasty model

Yang Kyung Cho  1 , Eun Young Shin  2 , Hironori Uehara  3 , Balamurali Ambati  3
Affiliations

Effect of itraconazole on the cornea in a murine suture model and penetrating keratoplasty model

Yang Kyung Cho et al. Int J Ophthalmol. .

Abstract

Aim: To investigate the anti-(lymph)angiogenic and/or anti-inflammatory effect of itraconazole in a corneal suture model and penetrating keratoplasty (PK) model.

Methods: Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among itraconazole, amphotericin B, dexamethasone, phosphate buffered saline (PBS) and surgery-only groups following subconjunctival injection in mice that underwent PK and corneal suture. Immunohistochemical staining and analysis were performed in each group. Real-time polymerase chain reaction (RT-PCR) was performed to quantify the expression of inflammatory cytokines (TNF-alpha, IL-6) and vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGFR-2, and VEGFR-3.

Results: In the suture model, the itraconazole group showed less angiogenesis, less lymphangiogenesis, and less inflammatory infiltration than the PBS group (all P<0.05). The itraconazole group showed reduced expression of VEGF-A, VEGFR-2, TNF-alpha, IL-6 than the PBS group (all P<0.05). In PK model, the two-month graft survival rate was 28.57% in itraconazole group, 62.50% in dexamethasone group, 12.50% in PBS group, 0 in amphotericin B group and 0 in surgery-only group. Graft survival in the itraconazole group was higher than that in the amphotericin, PBS and surgery-only group (P=0.057, 0.096, 0.012, respectively). The itraconazole group showed less total angiogenesis and lymphangiogenesis than PBS group (all P<0.05).

Conclusion: Itraconazole decrease neovascularization, lymphangiogenesis, and inflammation in both a corneal suture model and PK model. Itraconazole has anti-(lymph)-angiogenic and anti-inflammatory effects in addition to its intrinsic antifungal effect and is therefore an alternative treatment option in cases where steroids cannot be used.

Keywords: amphotericin B; dexamethasone; graft survival; itraconazole; lymphangiogenesis; neovascularization.

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Figures

Figure 1
Figure 1. Grading of corneal neovascularization and biomicroscopic pictures (itraconazole, amphotericin B, dexamethasone, PBS, suture-only groups).
Figure 2
Figure 2. NV in suture model
A: Comparison of NV in the corneal suture model among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, suture-only groups) at 6wk post-sutures; B: Representative pictures. aP<0.05, bP<0.01.
Figure 3
Figure 3. LY in suture model
A: Comparison of LY in the corneal suture model among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, suture-only groups) at 6wk post-sutures; B: Representative pictures. aP<0.05.
Figure 4
Figure 4. Inflammatory infiltration in suture model
A: Comparison of inflammatory infiltration in the corneal suture model among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, suture-only groups) at 6wk post-sutures; B: Representative pictures. aP<0.05, bP<0.01.
Figure 5
Figure 5. Comparison of mRNA expression among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, suture-only groups) at 6wk post-sutures
A: VEGF-A; B: VEGF-C; C: TNF-alpha; D: IL-6; E: VEGFR-2; F: VEGFR-3. mRNA expression ratios were normalized by GAPDH (PBS group=1.0). aP<0.05, bP<0.01 compared with PBS.
Figure 6
Figure 6. Comparison of graft survival among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, KP-only groups).
Figure 7
Figure 7. Biomicroscopic pictures of cornea after PK in five groups (itraconazole, amphotericin B, dexamethasone, PBS, KP-only groups).
Figure 8
Figure 8. NV in PK model
A: Comparison of NV in the PK model among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, KP-only groups) at 8wk post-PK; B: Representative pictures. aP<0.05, bP<0.01.
Figure 9
Figure 9. LY in PK model
A: Comparison of LY in the PK model among the five groups (itraconazole, amphotericin B, dexamethasone, PBS, KP-only groups) at 8wk post-PK; B: Representative pictures. aP<0.05, bP<0.01.
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