Primary Mechanisms of Thymosin β4 Repair Activity in Dry Eye Disorders and Other Tissue Injuries

Abstract

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.

The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options

“…97 However, multiple secondary end points showed improvements with RGN-259 in the phase 2 trial and a recently completed phase 3 trial (NCT02974907). [97][98][99][100] Conclusion DED is a multifactorial disease that is characterized by a sustained inflammatory response on the ocular surface that, if left untreated, can lead to chronic disease. Whether DED can be considered ''progressive''-that is, whether any clinical characteristics of DED will progress without treatment-remains to be determined.…”

Proteomic analysis of tears following acupuncture treatment for menopausal dry eye disease by two-dimensional nano-liquid chromatography coupled with tandem mass spectrometry

“…Dry eye has many causes, including inflammation and apoptosis, and anti-inflammation and ocular surface repair have proven to be useful in treating this condition. 15 Proteins involved in transport, signal transduction, and regulation were found to be upregulated, and cell components and proliferation-related proteins were relatively downregulated. This interesting phenomenon suggests that acupuncture and artificial tear treatment may increase protein synthesis.…”

A Tobacco-Derived Thymosinβ4 Concatemer Promotes Cell Proliferation and Wound Healing in Mice

“…The sequence LKKTET of the 43-amino acid T β 4 protein, which is strongly conserved between all β -thymosins, represents the “actin-binding motif” and is similar to the sequence of WH2 domains (Wasp Homology Domain 2, a name derived from the Wiskott-Aldrich syndrome protein) [ 40 ]. Previous research has suggested that T β 4 may be useful for treating hard-to-heal wounds, including diabetic ulcers, bedsores and damaged corneas, and heart muscle injured by heart attacks and tumor biomarkers, as well as for curing various skin, central nervous system, and lung diseases [ 5 , 10 , 14 , 17 , 18 , 21 – 23 ]. Consequently, there is great interest in the use of T β 4 in clinical applications.…”

“…In addition to regulating actin formation, extracellular T β 4 participates in several biological processes, including blood coagulation, osteoblast differentiation, activation and degranulation of platelets, and regulation of cell migration ( http://www.ncbi.nlm.nih.gov/gene/7114 ). T β 4 therefore plays an important role in medical treatments, such as anti-inflammation [ 6 ], angiogenesis [ 7 , 8 ], remodeling of damaged tissues [ 9 , 10 ], and the prevention of organic fibrogenesis [ 5 , 11 , 12 ].…”

“…Several studies have demonstrated that the expression of Tβ4 is upregulated in injured tissue and differentiating cells [ 13 , 14 ], and high concentrations of T β 4 protein have been found in blood platelets, wound fluid, and a range of tissues [ 15 , 16 ] and its effects appear to be widespread. It has been extensively employed to treat diabetic ulcers and bedsores [ 17 , 18 ] and damaged corneas [ 10 , 19 , 20 ] and for cardiac cell survival and the repair of heart muscle injured during heart attacks [ 9 , 21 , 22 ], as well as antifibrogenesis of the liver [ 5 ], kidney [ 11 , 23 ] and lung [ 12 ]. T β 4 therefore shows great promise for numerous clinical applications [ 17 ] and the resulting increased commercial demand relies on efficient production methods.…”