Persistent corneal wounds with epithelial defects pose therapeutic challenges to the clinician and can result in ocular morbidity, visual damage, and increase the patient's risk for potential eye loss. Currently, there are no approved clinical treatments that accelerate and/or promote corneal epithelial healing therefore limiting therapeutic options for corneal epithelial defects to providing merely an environment conducive for healing. Thus, an agent that enhances corneal repair without significant untoward effects would be a major therapeutic advance, particularly for corneal alkali burns. Thymosin B4 (TB4), a 43 amino acid protein, accelerates full thickness wound repair in the skin of normal and healing-impaired rats and stimulates keratinocyte migration in vitro (Malinda et al., 1999). In preliminary studies in rats, the applicant showed that TB4 accelerated corneal re-epithelialization, decreased inflammation in vivo and promoted human corneal epithelial cell migration in vitro. In other experiments, the applicant found that TB4 also decreased corneal polymorphonuclear leukocyte (PMN) infiltration and cytokine levels in a murine alkali burn model at 7 days post bum. However, the mechanism(s) by which TB4 exerts these effects is unknown. The goal of the studies proposed herein is to elucidate mechanisms by which TB4 promotes corneal repair and regulates inflammation. This proposal will test the overall hypothesis that TB4 promotes corneal wound repair by its anti-inflammatory effects.
The aims of this study are: 1) To test the hypothesis that TB4 decreases corneal PMN infiltration after moderate (non-perforating) and severe (cornea perforates) alkali bum by altering production of cytokines and chemokines; 2) To test the hypothesis that TB4 regulates cytokine and chemokine production in cultured human corneal cells (epithelial and keratocytes); 3) To test the hypothesis that TB4 regulates PNIN production of soluble mediators of inflammation and proteases. Using in vivo and in vitro model systems to analyze the mechanism(s) of TB4 activity, the proposed studies are highly relevant to the possible clinical application of TB4 in the treatment of corneal epithelial wound healing disorders.
