thymosin-beta(4) and Eye-Injuries

Dry eye disorders are becoming more common due to many causes, including an aging population, increased pollution, and postrefractive surgery. Current treatments include artificial tears; gels; lubricants; tear duct plugs; and anti-inflammatory agents such as steroids, doxycycline, and cyclosporine. For more severe forms of the disease, serum tears and scleral contact lenses are employed. Despite these therapies, successful resolution of the problem is limited because none of these treatments fully addresses the underlying causes of dry eye to promote ocular surface repair. Thymosin β4 (Tβ4), a small, naturally occurring protein, promotes complete and faster corneal healing than saline alone or prescription agents (doxycycline and cyclosporine) in various animal models of eye injury. In human trials, it improves both the signs and symptoms of moderate to severe dry eye with effects lasting beyond the treatment period. This review will cover the multiple activities of Tβ4 on cell migration, inflammation, apoptosis, cytoprotection, and gene expression with a focus on mechanisms of cell migration, including laminin-332 synthesis and degradation, that account for this paradigm-shifting potential new treatment for dry eye disorders. We will also speculate on additional mechanisms that might promote eye repair based on data from other tissue injury models. Such studies provide the rationale for use of Tβ4 in other types of eye disorders beyond dry eye. Finally, we will identify the gaps in our knowledge and propose future research avenues.

Topics: Animals; Dry Eye Syndromes; Eye Injuries; Humans; Thymosin; Wound Healing

Exposure of tissues to sulfur mustard (SM) results in the formation of protein and nucleotide adducts that disrupt cellular metabolism and cause cell death. Subsequent pathologies involve a significant proinflammatory response, disrupted healing, and long-term defects in tissue architecture. Following ocular exposure, acute corneal sequelae include epithelial erosions, necrosis, and corneal inflammation. Longer term, a progressive injury becomes distributed throughout the anterior chamber, which ultimately causes a profound remodeling of corneal tissues. In many cases, debilitating and vision-threatening injuries reoccur months to years after the initial exposure. Preliminary data in humans suffering from chronic epithelial lesions suggest that thymosin beta4 (Tbeta4) may be a viable candidate to mitigate acute or long-term ocular SM injury. To evaluate therapeutic candidates, we have developed a rabbit ocular exposure model system. In this paper, we report molecular, histological, ultrastructural, and clinical consequences of rabbit ocular SM injury, which can be used to assess Tbeta4 efficacy, including timepoints at which Tbeta4 will be assessed for therapeutic utility.

Topics: Animals; Cornea; Eye; Eye Injuries; Humans; Male; Mice; Mustard Gas; Necrosis; Physiological Phenomena; Rabbits; Thymosin; Wound Healing

Persistent corneal epithelial defects and inflammation within the central cornea can directly distort visual acuity and may lead to permanent visual loss. Therefore, treatments with agents that enhance corneal reepithelialization and regulate the inflammatory response without the deleterious side effects of currently used agents such as corticosteroids would result in improved clinical outcome and would represent a major advance in the field. Despite much progress in the areas of corneal wound healing research, clinically available pharmacological therapies that can promote repair and limit the visual complications from persistent corneal wounds are severely limited and remains a major deficiency in the field. Prior studies from our laboratory have demonstrated the potent wound healing and anti-inflammatory effects of thymosin beta4 (Tbeta(4); Tbeta4) in numerous models of corneal injury. We are studying the mechanisms by which Tbeta(4) suppresses inflammation and promotes repair. Herein, we discuss some of our new basic scientific directions that may lead to the use of Tbeta(4) as a novel corneal wound healing and anti-inflammatory therapy.

Topics: Adrenal Cortex Hormones; Animals; Corneal Diseases; Corneal Injuries; Eye Injuries; Forecasting; Inflammation; Mice; Thymosin; Wound Healing

Abnormalities in corneal reepithelialization caused by second-hand cigarette smoke (CS) are less known than the effects of CS on other tissues. The effects of CS on corneal epithelial cell migration and associated signaling mechanisms were examined, to determine the mechanisms by which CS delays corneal wound healing.. Corneal epithelial cells in two-dimensional or organ culture were exposed to sidestream whole (SSW) smoke, a major component of second-hand CS. Thymosin beta 4 (Tbeta4), a molecule thought to promote wound healing in the cornea, was tested to determine whether it can reverse the adverse effects of SSW smoke on corneal healing.. Cell migration, actin reorganization, and phosphorylation of focal adhesion kinase (FAK) and paxillin were all inhibited by exposure to SSW smoke, and the distribution of phospho-src in the cells was disrupted. Activation of RhoA, an important regulator of the cytoskeleton during cell migration, was also inhibited. Tbeta4 stimulated corneal epithelial cell migration in the presence of SSW smoke in culture and in vivo, and it partially reversed the inhibition of corneal healing by SSW smoke. However, Tbeta4 plus dexamethasone, an inhibitor of inflammation, together, reversed the effects of SSW smoke on corneal healing.. These findings suggest that SSW smoke exerts its effects on cell migration during corneal epithelial healing through inhibition of actin reorganization, activation of focal adhesion molecules, formation of the focal adhesion complex, and activation of Rho-GTPases. Furthermore, they strongly suggest that corneal injury induced by toxicants can be treated using anti-inflammatory agents coupled with Tbeta4.

Topics: Actins; Administration, Topical; Animals; Anti-Inflammatory Agents; Cell Division; Cell Movement; Dexamethasone; Drug Therapy, Combination; Epithelium, Corneal; Eye Injuries; Focal Adhesion Protein-Tyrosine Kinases; Humans; Immunoblotting; Immunoprecipitation; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Organ Culture Techniques; Paxillin; Phosphorylation; rhoA GTP-Binding Protein; Thymosin; Tobacco Smoke Pollution; Wound Healing

Topics: Animals; Cell Movement; Clinical Trials as Topic; Corneal Injuries; Eye Injuries; Humans; Myocardial Infarction; Neoplasms; Neovascularization, Physiologic; Thymalfasin; Thymosin; Wound Healing