Investigating the Effect and Mechanism of Histatin-5 Peptide in Relevant Models of Dry Eye

Dry eye disease (DED) is a common ocular surface disease that is vision threatening and lowers the quality of life of patients stricken with this complex disease. The currently available management options for DED are palliative measures including tear replenishment approaches that provide temporary relief of symptoms and anti-inflammatory medications that have limited efficacy and intolerable side effects with continued use. As such, there exists a great need to develop new effective and safe therapeutics, to resolve the burden of DED. Histatins (Hsts) are a family of antimicrobial peptides that have been shown to enhance oral wound healing and reduce mucosal inflammation. It has been noted that DED pathophysiology has commonalities with oral and mucosal surface inflammatory diseases. Therefore, given their epithelial pro-wound healing, anti-inflammatory and anti-infective effects, we chose to explore the utility of Hst peptides in treating ocular surface DED. Hst5 peptide is one of the more abundant and most potent Hsts that are known and was the focus of the present study. The aims of this research were to investigate the effect of Hst5 peptide in ameliorating mixed mechanism DED phenotype, evaluate its epithelial trophic action and elucidate the mechanism of action of Hst5 in the treatment of inflammation associated with DED. Using well-established models of dry eye including scopolamine and desiccating stress in C57BL/6 mice, and hyperosmolar NaCl solution challenge in human corneal epithelial cells, we demonstrated that Hst5 peptide treatment in-vivo, significantly protected corneal epithelial function, prevented goblet cell density loss, Suppressed CD45+ immune cells infiltration and inhibited epithelial cell apoptosis. Moreover, Hst5 peptide treatment in-vitro, significantly restored epithelial viability, mitigated inflammatory cytokine production associated with DED, through modulation of MAPK and NFκB signaling pathways, and reduced apoptotic mediators. This undertaken research is innovative as it is the first of its type to examine the use of Hst5 peptide as a potential novel treatment for DED. Hst5 may represent a new class of efficacious therapeutic agents against DED, demonstrating pro-epithelial and anti-inflammatory functions, in addition to possessing anti-microbial properties and being non-toxic.