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Differential Regulation of Key Stages in Early Corneal Wound Healing by TGF-ß Isoforms and Their Inhibitors

¹From the Cell and Molecular Unit, School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom; the ²Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Cardiff, United Kingdom; and ³Cambridge Antibody Technology, Cambridge, United Kingdom.

PURPOSE. Inhibition of TGF-ß reduces myofibroblast differentiation and fibrosis in the cornea. Determining the actions of distinct TGF-ß isoforms and their inhibitors during early corneal wound healing is an essential step in guiding therapeutic intervention.

METHODS. Bovine serum-free corneal cell and wounded organ cultures were challenged with a range of concentrations of TGF-ß₁, -ß₂, and -ß₃; IL-10; and neutralizing human monoclonal antibodies (mAbs) against TGF-ß₁ (CAT-192) or -ß₂, (CAT-152). Cultures were assessed for re-epithelialization, proliferation (cell counts and cresyl violet assay), morphology (histologic examination), repopulation of the area under the wound, and myofibroblast transformation (-smooth muscle actin) between 0 and 5 days.

RESULTS. TGF-ß₁ delayed re-epithelialization, increased repopulation of the stroma, increased keratocyte proliferation and was the only isoform to promote myofibroblast differentiation. The anti-TGF-ß₁ mAb, CAT-192 promoted re-epithelialization and reduced repopulation of the stroma. Exogenous TGF-ß₃ had little effect on re-epithelialization but reduced repopulation of the stroma. IL-10 promoted corneal re-epithelialization at low doses but inhibited this response at high doses. Stromal repopulation was prevented by all doses of IL-10. TGF-ß₂ or the anti-TGF-ß₂ mAb, CAT-152 had little effect on any repair parameter.

CONCLUSIONS. The results confirm TGF-ß₁ as the principal isoform in corneal wound healing and suggest that inhibition of the action of TGF-ß₁ can promote corneal wound healing. Treatment with the anti-TGF-ß₁ mAb CAT-192 accelerates corneal re-epithelialization but reduces cell repopulation of the stroma. The cytokines TGF-ß₃ and IL-10 have opposing actions to that of TGF-ß₁.

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