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Increased Expression of Inflammatory Cytokines and Matrix Metalloproteinases in Pseudophakic Corneal Edema

¹From the Departments of Ophthalmology and ²Pathology, Hadassah University Hospital, the Hebrew University–Hadassah School of Medicine, Jerusalem, Israel.

PURPOSE. To evaluate the expression of inflammatory cytokines and matrix metalloproteinases in the corneal epithelium in pseudophakic corneal edema (PCE).

METHODS. Tissue sections were prepared from formalin-fixed, paraffin-embedded blocks of corneal buttons removed from 20 patients with PCE during penetrating keratoplasty (PKP) and from 11 age-matched control eyes enucleated because of uveal melanoma. Expression of interleukin (IL)-1ß, -6, and -8; vascular endothelial growth factor (VEGF); and matrix metalloproteinase (MMP)-1, -3, and -9 proteins in the corneal epithelium was evaluated by immunohistochemistry. Digital image analysis was performed to quantify the expression of the various cytokines and MMPs. A mean intensity stain index (ISI), based on the staining density and the area stained, was calculated from digital images captured from sequential areas of the corneal epithelium.

RESULTS. The expression of most of the inflammatory cytokines and MMPs was significantly higher in the corneal epithelium of PCE corneal buttons than in the control specimens. MMP-9 had the highest expression when compared with the control (ISI = 55.08 ± 23.71 in PCE compared with 0.169 ± 0.156 in the control; P < 0.0001). Significantly higher ISIs were also recorded for MMP-1 (16.14 ± 8.49 vs. 1.13 ± 1.79; P < 0.0001), IL-1ß (62.62 ± 27.23.97 vs. 1.61 ± 1.27; P < 0.0001), IL-8 (37.91 ± 21.18 vs. 4.24 ± 3.60; P < 0.0001), and VEGF (81.67 ± 26.22 vs. 19.40 ± 16.85; P = 0.0001). The expression of MMP-3, IL-6, and TNF- in PCE was not different from control expression. Significant positive correlations were found between the expression of IL-1ß and MMP-9 (r² = 0.37; P = 0.015), between VEGF and IL-8 (r² = 0.22; P = 0.042), and a significant correlation was found between the expression of MMP-3 and TNF- (r² = 0.5197; P = 0.0007). The expression of TNF- correlated significantly with the patient’s age (r² = 0.28; P = 0.0195).

CONCLUSIONS. The corneal epithelium in PCE expresses high levels of cytokines and matrix-degrading enzymes, which are associated with inflammation, wound healing, angiogenesis, and tissue degradation. The expression of these mediators may partially explain the pathologic features associated with this disease, such as bulla formation, recurrent epithelial desquamation, and corneal neovascularization.

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