Download Inflammation in Dry Eye and Corneal Wound Healing

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
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“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
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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
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Cornea
Conjunctiva
Meibomian glands
Main and accessory lacrimal glands
Connecting neural network
IV) Pathophysiology of Dry Eyes
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Inflammatory process
Increased expression of inflammatory cytokines
Immunologic adhesion molecules
Sjogren’s syndrome
Ocular rosacea
Stevens-Johnson syndrome
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Neurotrophic process
LASIK
Reflex Arc Controlling Tear Production
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Ocular surface
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CN V (Trigeminal nerve)
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Brain stem
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CN VII (Facial nerve)
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Lacrimal gland
The Healthy Tear Film
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A delicate balance
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Lipid, aqueous & mucin components
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Outer lipid layer prevents evaporation
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Aqueous component – a complex mixture of proteins, mucins, and electrolytes
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Mucins provide viscosity and stability during the blink cycle
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Antimicrobial proteins: lysozyme, lactoferrin
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Growth factors & suppressors of inflammation: EGF, IL-1RA
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Soluble mucin 5AC secreted by goblet cells provides viscosity
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Electrolytes for proper osmolarity
Dry Eye Disease
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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
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Inflammatory cytokines
Growth and neural factors
MMPs
HLA-DR
Androgens
Cytokines
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Nonantibody protein
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Modulates inflammatory response
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Elevated levels of inflammatory cytokines in patients with Sjögren’s syndrome
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Decreased levels of epidermal growth factor
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Interleukins (IL-1a, IL-6, IL-8)
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Tumor necrosis factor A
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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
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VI) Autoimmune Disease and Being Female: Is there a Link?
VII) Paradigm change in dry eye therapy
Current Dry Eye Therapy
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Mainly palliative
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Tear replacement
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Doesn’t address underlying inflammation
Artificial Tears
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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
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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
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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
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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
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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
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