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Inflammation: A Shifting Prospective on Dry Eye Disease Abstract Emerging research has allowed a clearer understanding of the interaction of inflammation and cellular communication in dry eye disease. Additionally, the role hormones, female gender and the heightened autoimmune mediated response in dry eye, and other autoimmune diseases are becoming increasingly understood. Effective methods of inflammation modulation for the clinical setting are presented. Learning Objectives 1. Understand the effect of inflammation in dry eye disease 2. Learn how modulation of inflammation can be utilized in the clinical setting 3. Present current research, which increases our understanding of the linkage between female gender and autoimmune diseases. 4. Learn which patients would benefit from these emerging treatments Outline I) Emerging Definition of Dry Eyes “A disorder whereby dysfunction of the lacrimal functional unit causes unstable tear film which in turn promotes ocular surface inflammation, epithelial disease, and symptoms of discomfort” II) Prevalence of Dry Eye Who is most likely to have dry eye? Which patients are candidates for therapy? How does dry eye effect patient’s quality of life? III) Keratoconjunctivitis Sicca vs Lacrimal Keratoconjunctivitis The Lacrimal Functional Unit Cornea Conjunctiva Meibomian glands Main and accessory lacrimal glands Connecting neural network IV) Pathophysiology of Dry Eyes Inflammatory process Increased expression of inflammatory cytokines Immunologic adhesion molecules Sjogren’s syndrome Ocular rosacea Stevens-Johnson syndrome 1 Neurotrophic process LASIK Reflex Arc Controlling Tear Production Ocular surface CN V (Trigeminal nerve) Brain stem CN VII (Facial nerve) Lacrimal gland The Healthy Tear Film A delicate balance Lipid, aqueous & mucin components Outer lipid layer prevents evaporation Aqueous component – a complex mixture of proteins, mucins, and electrolytes Mucins provide viscosity and stability during the blink cycle Antimicrobial proteins: lysozyme, lactoferrin Growth factors & suppressors of inflammation: EGF, IL-1RA Soluble mucin 5AC secreted by goblet cells provides viscosity Electrolytes for proper osmolarity Dry Eye Disease Tear components in patients with dry eye differ in quantity and quality from normal tears Lactoferrin levels are significantly lower in dry eye patients than in controls Epidermal growth factor is significantly decreased in dry eye patients These findings were consistent regardless of autoimmune status (Sjögren's and non-Sjögren's) V) Inflammation and dry eyes The Players: The Short List Inflammatory cytokines Growth and neural factors MMPs HLA-DR Androgens Cytokines Nonantibody protein Modulates inflammatory response Elevated levels of inflammatory cytokines in patients with Sjögren’s syndrome Decreased levels of epidermal growth factor Interleukins (IL-1a, IL-6, IL-8) Tumor necrosis factor A 2 Apoptosis The precise pathway by which apoptosis occurs in dry eye has not yet been fully elucidated May play an important role in its pathogenesis and in the clinical treatment of LKC VI) Autoimmune Disease and Being Female: Is there a Link? VII) Paradigm change in dry eye therapy Current Dry Eye Therapy Mainly palliative Tear replacement Doesn’t address underlying inflammation Artificial Tears Artificial tears contain electrolytes, Lack the complex mixture of proteins, mucins and other factors found in healthy tears Provide only temporary, palliative relief A majority of patients (74%) do not obtain satisfactory relief from dry eye symptoms with artificial tears Punctal plugs are not effective for all patients and may be counter indicated Many dry eye patients (34%) wish there was an effective therapy available for treating their dry eyes Advances in Dry Eye Therapy Topical androgens Steroids NSAIDS Dietary fatty acid supplements TNF antagonists Cyclosporin A Peptides growth factors and vitamins Autologous serum tear replacement Cevimeline (muscarinic acetylcholine agonist) Diquafosol tetrasodium (P2Y2 agonist) Topical gefarnate Trehalose eye drops Cyclosporine CsA Therapeutic mechanisms of cyclosporin A in dry eye could be inhibition of mitochondrial pathways of apoptosis Has been reported to prevent the mitochondrial changes that precedes apoptotic cell death Cyclosporine is a naturally occurring fungal metabolite widely used as an immunosuppressant in human organ recipients 3 Immunosuppressive mechanisms of cyclosporine may relate to binding of specific proteins required for initiation of T-cell activation preventing T-cell production of inflammatory cytokines such as interleukin (IL)-2 and IL-4 disrupts the immune-mediated processes cascade Blocks the activation of the signaling pathways, which are triggered by antigen recognition Highly specific inhibition of T-cell activation Key Learning from the Restasis® Clinical Trials Decreased reliance on artificial tears Increased goblet cell density vs vehicle Decreased T-cells in both Sjögren’s and Non-Sjögren’s patients Restasis® Reduces Indicators of Inflammation vs Vehicle Decreased expression of HLA-DR and CD11a markers of immune activation VIII) Conclusions: IX) References Ang RT, Dartt DA, Tsubota. 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