Abstract
Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. In this study, a newly developed trypsin-like serine protease inhibitor (UAMC-00050) in a tear drop formulation was evaluated to treat ocular inflammation. A surgical animal model of dry eye was employed to investigate the potential of UAMC-00050 on dry eye pathology. Animals treated with UAMC-00050 displayed a significant reduction in ocular surface damage after evaluation with sodium fluorescein, compared to untreated, vehicle treated and cyclosporine-treated animals. The concentrations of IL-1α and TNF-α were also significantly reduced in tear fluid from UAMC-00050-treated rats. Additionally, inflammatory cell infiltration in the palpebral conjunctiva (CD3 and CD45), was substantially reduced. An accumulation of pro-MMP-9 and a decrease in active MMP-9 were found in tear fluid from animals treated with UAMC-00050, suggesting that trypsin-like serine proteases play a role in activating MMP-9 in ocular inflammation in this animal model. Comparative qRT-PCR analyses on ocular tissue indicated the upregulation of tryptase, urokinase plasminogen activator receptor (uPAR) and protease-activated receptor 2 (PAR2). The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity. These results provide a proof-of-concept for the in vivo modifying potential of UAMC-00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation.
Highlights
Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options
Dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms in which tear film instability and hyperosmolarity ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles (TFOS DEWS II)[1]
A positive trend was observed for Cyclosporin A (CyA) and UAMC-00050, these results were not statistically significant
Summary
Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity These results provide a proof-of-concept for the in vivo modifying potential of UAMC00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation. Serine proteases play a pivotal role in several inflammatory conditions and have come in the spotlight as therapeutic targets for many diseases with an inflammatory component like keratitis, arthritis, vasculitis, asthma, cancer, multiple sclerosis and fibrosis[20,21,22,23,24,25,26,27,28,29] They have the ability to promote inflammatory protein expression and have a direct influence on the degradation of extracellular matrix components, loss of epithelial barrier function and MMP-9 a ctivation[20,21,22,23,24]. Because these pathological processes occur in DES-associated inflammation, we hypothesize the involvement of certain serine proteases in this disorder
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