The anti-inflammatory compounds resveratrol and quercetin as therapeutic agents for immune-based ocular surface diseases / compuestos antiinflamatorios resveratrol y quercitina como agentes terapéuticos para las enfermedades de base inmune de la superficie ocular

Abstract

The aim of this thesis was to investigate the effect of two major natural compounds, resveratrol and quercetin, and their combination on cells involved in the inflammatory response at the ocular surface, as well as their potential therapeutic effects for dry eye disease. For this purpose, the anti-inflammatory and anti-oxidant effects of resveratrol, quercetin and their combination were tested in two ocular surface (conjunctival and corneal) epithelial cell lines stimulated by the pro-inflammatory cytokine TNF-¿ and UV B light. After that, their immunoregulatory effects were determined in activated peripheral blood mononuclear cells. Their anti-inflammatory effects (by topical application) were further studied in a murine model of dry eye induced by desiccating stress, followed by an adoptive transfer model using athymic mice. Additionally, their anti-allergic effects were determined in activated cord blood-derived mast cells. Results showed that resveratrol, quercetin and their combination can decrease cytokine secretion (IL-6, IL-8/CXCL8 and IP-10/CXCL10) and COX-2 expression induced by TNF-¿, and free radical production induced by UV-B light in conjunctival and corneal epithelial cells. The combination of both compounds modulated proliferation of peripheral blood mononuclear cells. In addition, both compounds (separately and combined) decreased cytokine production and corneal fluorescein staining in mice exposed to desiccating stress, as well as CD4+ T cell infiltration in conjunctiva of athymic mice. Finally, resveratrol, quercetin and their combination inhibited histamine secretion and cytokine/chemokine production by activated mast cells. In conclusion, resveratrol, quercetin and their combination can modulate the response of cells involved in inflammatory processes at the ocular surface such as dry eye and ocular allergy. In addition, topical application of resveratrol, quercetin and their combination in experimental dry eye leads to improved clinical signs and inflammation associated with the ocular surface, showing their potential therapeutic properties for treating dry eye disease.