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Ophthalmology > Day 3 (2): Physiology, Immunology and Wound Healing of the Cornea, Conjunctiva and Ocular Surface > Flashcards

Day 3 (2): Physiology, Immunology and Wound Healing of the Cornea, Conjunctiva and Ocular Surface Flashcards

1
Q

Factors that contribute to corneal transparency?

A
  1. Collagen fibrils uniform in size, equidistant from each other and regularly arranged.
  2. Deturgescence: state of relative dehydration (78% water)
  3. Avascular
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2
Q

Responsible for the avascularity of the cornea?

A

Sflt-1/Soluble VEGF-1 Receptor
- suppresses VEGF-A, an angiogenic factor present in the cornea that stimulates development of new vessels
- inactivation of Sflt-1 by antibodies or other pathologic conditions abolishes avascularity of the cornea

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3
Q

What are the nutrition sources of the cornea?

A

Glucose: aqueous humor by diffusion through endothelium

Oxygen: precorneal tear film by diffusion through epithelium
- absorbed from the air and eyelid vasculature
- tear film must always be directly exposed to the atmosphere

Glucose –> Pyruvic Acid –>

Awake (eyes open): (+) Oxygen –> Aerobic –> Krebs Cycle
Asleep (eyes closed): (-) Oxygen –> Anaerobic –> Lactic Acid

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4
Q

Common complication of contact lens with low Dk values

A

Low Dk values = stromal edema

Low Dk values –> poor oxygen permeability –> decreased oxygen diffusion in cornea –> corneal hypoxia –> dysfunction of the endothelial pump (oxygen needed by Na-K ATPase pump) which maintains corneal deturgescence –> stromal edema

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5
Q

Most widely used artificial cornea or keratoprosthesis.

A

Boston Keratoprosthesis

  • Treatment option for corneal disease not amenable to standard penetrating keratoplasty (PKP)
  • Prosthokeratoplasty: damaged cornea is replaced with an artificial cornea
  • Collar button design consisting of three components:
    1. Front plate with optical stem
    2. Back plate
    3. Titanium locking c-ring
  • Type II: reserved for severe end-stage ocular surface disease desiccation; similar to the type I device but requires a permanent tarsorrhaphy
  • Device is assembled with a donor corneal graft positioned between the front and back plate, that is then sutured into place in a similar fashion to PKP
  • Improvements in design:
    1. Addition of holes (16 holes) in the back plate: allows diffusion of nutritive aqueous to support donor graft stromal carrier and keratocytes
    2. Titanium locking c-ring: prevents intraocular disassembly
    3. Threadless: simplified assembly and less damage to the donor endothelium
    4. Titanium back plate: improves biocompatibility and retention; reduce complications (retroprosthetic membranes and stromal corneal melts)

Indications: conditions not amenable to traditional PKP
1. Multiple graft failures
2. Stevens-Johnson syndrome
3. Ocular cicatricial pemphigoid
4. Autoimmune diseases
5. Ocular burns (acid and alkali)
6. Aniridia
7. Herpetic keratitis

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6
Q

Describe the corneal epithelium.

A
  • 50 um thick (10% of the entire cornea)
  • (+) Microvilli: surface projections in apical side of the most superficial layer
  • (+) Glycocalyx: glycoprotein and glycolipid coating of the microvilli which interacts directly with the mucoaqueous layer of the tear film
    1. Stability of the tear film
    2. Wettability of the corneal surface
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7
Q

Differences between ocular surface of healthy eye and dry eye.

A

Healthy:
- Normal tear film composition
- Abundant glycocalyx
- (-) corneal staining with fluorescein dye

Dry Eye:
- Thin tear film
- Minimal glycocalyx
- Poor wettability and unstable tear film due to decreased glycocalyx –> multiple areas of corneal staining indication damage to the corneal surface

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8
Q

What are the different epithelial plasma membrane proteins and their functions?

A
  1. Facilitates wound healing mechanisms of the cornea through corneal epithelial sheet migration
  2. Sugar moeities of glycoproteins: attachment sites for microbes
  3. Serve as junctional complexes

Barrier function:
1. Desmosomes: attaches epithelial cells to each other
2. Tight junctions: prevent passage of external agents into the deeper layers of the cornea; in S cell layer
3. Adherens junctions: prevent passage of external agents into the deeper layers of the cornea; in S cell layer

Nutritional function:
Gap junction: allows passage of small molecules between cells; in W and B cell layer

Anchoring function:
Hemidesmosomes: attachment of cells to the basement membrane
* Recurrent Corneal Erosion Syndrome
- epithelium spontaneously sloughs off due to poor adherence to the BM caused by abnormalities in the hemidesmosomes.

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9
Q

Describe the normal wound healing response of the corneal epithelium.

A

Epithelial Cell Migration: 2 mm/day
- affected by preservatives in eyedrops (Benzalkonium chloride)

Limbal stem cells –> Transient Amplifying (TA) Cells –> Basal Cells –> Wing Cells –> Superficial Cells –> Desquamation into tears

Process:
1. MIGRATION: Limbal stem cells originating from the Palisades of Vogt in the Corneal-Conjunctival Zone or Corneal Limbus migrate centripetally towards the central cornea.

  1. DIFFERENTIATION: into TA cells and B cells of the epithelium
  2. PROLIFERATION: into W cells then S cells as it moves superficially into the upper layers.
  3. DESQUAMATION: in into tears
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10
Q

How do topical drugs penetrate the eye?

A

To penetrate into the anterior chamber: UNcharged molecule crossing the EPITHELIUM should be able to dissociate at physiologic pH and temperature to a CHARGED state at the STROMA.

Epithelium: hydroPHOBIC + tight junctions
- prevents entry of tears
- poor penetration of hydroPHILIC molecules (“like dissolves like”)
- to enter:

  1. Polar molecule < 500 Da
  2. UNcharged
  3. If with damaged or inflamed epithelium

Stroma: hydroPHILIC
- CHARGED state to enter stroma

E.g. Natamycin
- antifungal which poorly penetrates the the cornea
- epithelium is scraped to facilitate entry into stroma

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11
Q

What is the Bowman’s Layer and its function?

A
  • Acellular membrane-like layer
  • Anterior surface of the stroma
  • Condensation of RANDOMLY-ARRANGED collagen fibers and proteoglycans
  • Inelastic
  • DOES NOT regenerate
  • Function: prevent exposure of stromal keratocytes to growth factors secreted by the epithelial cells (TGF-B)

TGF-B: important for tissue repair (normal or fibrosis)

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12
Q

How does HSV Keratitis cause fibrosis and scarring of the stroma?

A

HSV destroys the Bowman’s Layer causing the exposure of the anterior stroma to TGF-B secreted by the healing epithelial cells.

Keratocytes (flattened, quiescent fibroblasts residing in between collagen lamellae of the stroma), once exposed to TGF-B, become activated, causing fibrosis and scarring.

Finding: Ghost Dendrite appearance

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13
Q

Thickest layer of the cornea

A

Stroma
- 90% of the thickness
- composed of ORGANIZED collagen lamellae/sheets with intervening proteins, proteoglycans, glycoproteins and keratocytes.
- 10-40% are keratocytes (DECREASES with age)
- mechanical properties of this layer define the mechanical properties of the entire cornea due to its thickness

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14
Q

Describe the normal wound healing process of the corneal stroma.

A

Homeostasis: formation of ECM = degradation of ECM
- maintained by the keratocytes through synthesis of collagen, GAGs and MMP

Formation of ECM:

Injury –> cytokine and growth factor production by epithelial cells + disruption of stromal integrity –> keratocytes activated to myofibroblasts –> normal healing OR fibrosis

Fibrosis: aberrant and excessive ECM production

Degradation of ECM

Keratocytes: produce MMP which degrade ECM components

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15
Q

Pathologic degradation of the ECM component of the corneal stroma

A

Keratolysis: seen in corneal ulcers

Possible culprits:
1. Collagenase: bacteria
2. MMP: activated keratocyte/myofibroblast
3. Protease: inflammatory cells
4. Elastase: P. aeruginosa
- degrades collagen directly and stimulation of MMP secretion by keratocytes

Treatment: Doxycycline/Tetracycline
- inhibits collagenase-initiated ECM breakdown

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16
Q

What is the orientation and arrangement of collagen fibrils in the different layers of the cornea?

A

Corneal thickness:
Central - 550 um
Peripheral - 700 - 1000 um

Bowman’s Layer - woven, RANDOM, fibril mat
Anterior 1/3 Stroma - woven, UNIDIRECTIONAL, OBLIQUE
Posterior 2/3 - NONwoven, UNIDIRECTIONAL, PERPENDICULAR
Descemet’s Membrane - HEXAGONAL lattice

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17
Q

Where are intrastromal corneal ring segments implanted?

A
  • Mid-corneal peripheral stroma around 2/3 of depth OUTSIDE the central optical zone
  • Reshape the anterior corneal surface while maintaining the prolate profile (positive asphericity) of the cornea.
  • Acts as spacer element between the bundles of corneal lamellae producing a shortening of the central arc length (arc shortening effect) that is proportional to the thickness of the device.
  • The central portion of the anterior corneal surface tends to flatten and the peripheral area adjacent to ring insertion is displaced forward
18
Q

Relate collagen structure of cornea and sclera to its effect on transparency

A
  • Cornea and Sclera have SIMILAR collagen composition
  • As you move away from the midcornea, collagen fibrils become more VARIABLE in size and become LESS DENSELY PACKED –> HETEROGENOUS APPEARANCE

Reasons for corneal transparency:
1. Collagen fibrils UNIFORM (homogenous) and NARROW in size
2. Collagen fibrils EQUIDISTANT from each other (55-60 um space)
3. COMPACT and REGULAR arrangement

Reasons for scleral opacity:
1. Fibrils are VARIABLE (heterogenous) in size and spacing
2. IRREGULARLY arranged and LESS DENSELY PACKED

19
Q

The basement membrane of the endothelial cell layer

A

Descemet’s Membrane
- 10-12 um thick
- Thickens with age (posterior non-banded zone): 3-4x thicker in adults
- Separates the stroma from the endothelium
- 2 zones:
1. Anterior banded zone: present at birth
2. Posterior non-banded zone: not present at birth but continuously produced by the endothelium with age

20
Q

Role of the corneal endothelium in maintaining corneal transparency.

A

Endothelium
- regulates corneal HYDRATION at 78% water by acting as a PUMP and corneal NUTRITION by acting as a LEAKY BARRIER
- BARRIER: covers the entire posterior surface of the cornea with NO GAPS –> leakage is controlled via tight junctions
- METABOLIC PUMP: maintain corneal deturgescence

Hydration:
- LEAK RATE = PUMP RATE to maintain hydration at 78%
- Leak Rate: leaky barrier via TIGHT JUNCTIONS in between cells
- Pump Rate:
1. Na-K-ATPase pump (membrane-bound)
2. Carbonic Anhydrase pathway (intracellular)

Nutrition:
- Aqueous Humor: major source of nutrients (especially GLUCOSE) for all layers of the cornea
- Leakiness of tight junctions is important for nutrition because cornea is AVASCULAR and has NO LYMPH VESSELS

21
Q

Conditions that alter corneal endothelial pump function and corneal transparency?

A
  1. Inhibition of Na-K-ATPase
    - low d/K (poorly O2-permeable) contact lenses or prolonged eyelid closure –> anaerobic metabolism –> acidic stromal pH (increased lactic acid and CO2) + HETE production by epithelium
  2. Decreased temperature
    - donor cornea should be thawed prior to transplant
  3. Carbonic anhydrase inhibitors (decreased bicarbonate)
    - carbonic acid increases due to non-conversion to bicarbonate –> acidic pH
  4. Mechanical and chemical injury –> decreased ECD
  5. Pathologic states
22
Q

ACUTE SEVERE intraocular INFLAMMATION accompanied by DIFFUSE corneal edema within 1-2 days of anterior segment surgery

A

Toxic Anterior Segment Syndrome
- most commonly associated with cataract surgery
- form of STERILE, NONINFECTIOUS ENDOPHTHALMITIS
- SX: (+/-) pain, (+) decrease in vision, (+) diffuse corneal edema that extends limbus to limbus, (+) photophobia, (+) severe anterior chamber reaction, (+/-) hypopyon.
- presents WITHIN 12-24 HOURS AFTER SURGERY (vs Infectious Endophthalmitis: 2-7 days after surgery)
- TX: Topical steroids

  • Corneal edema due to endothelial dysfunction (leak rate INCREASES but pump rate DECREASES) secondary to:
    1. Contamination of intraocular solution
    2. Abnormal PH, osmolarity or ionic composition of IO solution
    3. Denatured Ophthalmic Viscosurgical Devices (OVD)
    4. Intraocular antibiotics and topical ointments
    5. Inadequate sterilization of surgical instruments and tubing
    6. Inadequate flushing of instruments between cases –> build-up of OVD
    7. Preservatives
    8. Metallic precipitates
23
Q

Criteria for intraocular solutions to be biologically compatible with the endothelium.

A
  1. Electrolyte levels match those of AH
  2. Nutrition: Glucose
  3. Buffer: Bicarbonate
  4. Antioxidant: Glutathione
  5. pH: 6.7 - 8.1
  6. Osmolarity: 270 - 350 mOsm
  7. Nontoxic concentrations
  8. NO preservatives
24
Q

Corneal transparency is a balance between what 4 factors?

A
  • Dependent on corneal deturgescence (state of relative dehydration at 78% water)
  • Water moves from HYPOOSMOTIC (low solutes, higher water) stroma to HYPERTONIC (high solutes, lower water) AH

Normal Eyes:
1. IOP = Stromal Swelling Pressure
- Swelling pressure: anionic charge of GAGs and proteins repelling each other –> STROMAL EDEMA
- IOP: AH production and drainage –> EPITHELIAL EDEMA

  1. Endothelial Leaky Barrier Rate = Na-K-ATPase Pump Rate
    - Pump failure causes BOTH STROMAL AND EPITHELIAL EDEMA due to fluid diffusion

Examples:
1. Acute Glaucoma: IOP > stromal swelling pressure
- endothelium normal
- (+) epithelial edema BUT normal stroma

  1. Phthisis bulbi: stromal swelling pressure > IOP (zero)
    - (+) stromal edema BUT normal epithelium
  2. Bullous Keratopathy: pump failure due to defective endothelium
    - (+) BOTH epithelial and stromal edema due to fluid diffusion
25
Q

Normal ECD with age.

A

*Children: 3500 - 4000 cells/sq. mm
*Adult: 2000 - 3000 cells/sq. mm
*40 yo (average): 2600 cells/sq. mm
*Elderly: < 2000 cells/sq. mm
*Normal attrition rate: 0.5-0.6%/year
*Minimum ECD required: 400 - 700 cells/sq. mm

With aging:
- DECREASE ECD –> decrease Na-K-ATPase pump rate
- If still with enough ECD to function, can still pump fluid out of stroma –> SLIGHTLY HAZY cornea

Clues to decreasing ECD:
1. Polymegathism: remaining cells enlarge to cover areas of lost cells (VARIABLE SIZES)
- Na-K-ATPase pump located in basoLATERAL border of the cell
- Enlargement accompanied by THINNING and STRETCHING of the cell, surface area for the pump DECREASES –> decreased pump rate

  1. Pleomorphism: remaining cells alter shape to cover of lost cells areas (VARIABLE SHAPE)
26
Q

Functions of the conjunctiva

A
  1. BARRIER: to microbes and foreign bodies
  2. MOVEMENT: allows free rotation of globe
  3. NUTRITIVE: tear film maintenance and corneal epithelial health
    - regulates volume, osmolarity and tonicity

VS Cornea:
1. Epithelium is water-permeable; Corneal epithelium is hydrophobic and (+) tight and adherens junctions
2. Secretory: active transport of Cl coupled with fluid movement
- 50 uL/h (basal tear production with no involvement yet of accessory lacrimal gland secretion)

27
Q

1st ocular surface that light encounters

A

Tear Film
- its HIGHER refractive index (1.336) vs air (1.000) causes light to slow down and bend along the air-tear interface thus directing light towards the cornea

28
Q

Functions of the tear film

A
  1. Maintains smoothness of the optical surface for light transmission
  2. Medium for diffusion of oxygen and nutrients from the air and eyelid vasculature to conjunctiva and cornea
  3. Barrier and medium for removal of debris
29
Q

Current two-phase model of the tear film

A
  1. Lipid layer: prevents tear evaporation and collapse
    - Meibum: secreted by the Meibomian glands
  2. Muco-Aqueous Layer: distributes nutrition to the ocular surface
    - Aqueous: secreted by Lacrimal Glands
    - Mucus: secreted by Goblet Cells at the Crypts of Henle
30
Q

Pertinent characteristics of the tear film

A

Water content: 98%
Thickness (both layers): 3.4 um thick
Thickness (lipid layer): 15 - 160 nm thick
Volume (UNanesthetized): 7.4 uL (REFLEX + BASAL)
Volume (ANESthetized): 2.6 uL (BASAL only)
Secretory rate and volume decreases with age (hypolacrimation starts at 40 yo) and anesthesia
Turnover rate: 15%/min
Osmolarity: ~ 300 mOsm/L
pH: 6.5 - 7.5

31
Q

What produces the Lipid Layer of the tear film?

A

Meibomian Glands
- Sebaceous glands located in the tarsal plates
- Product: Meibum
- Upper lid > lower lid (30-40 vs 20-30 thus more secretions)
- DO NOT have direct contact with eyelash follicles (compared to sebaceous glands in other parts of the skin)
- Blinking (mechanical action of pretarsal OO) releases meibum into the lid margin
- Riolan’s muscle: contraction compresses terminal ducts to deliver Meibum onto the lid margin and prevents overflow
- Opening: between Mucocutaneous Junction and Gray Line (Riolan’s Muscle)

Riolan’s Muscle/Pars Ciliaris: marginal portion of the palpebral OO adjacent to the eyelid margin

Functions:
1. Prevents evaporation of underlying mucoaqueous layer
2. Stabilize the tear film by lowering surface tension

32
Q

Findings in tear film instability

A
  1. Tear Break Up Time:
    - Normal: >/= 10 seconds
    - Suspicious: 5 - 9 seconds
    - Short: < 5 seconds
    - Lipid layer prevents quick breaking up of tears through evaporation
  2. Lipid layer melting point: 32-40 degrees Celsius
    - Normal: 32 degrees Celsius (low melting point, clear, runny & oily)

Pathology:
Meibomian Gland Dysfunction/Inspissation
- E.g. Chronic Marginal Blepharitis
- Higher melting point of lipid layer –> pasty, thick and stagnant
- Not applied and distributed well over the ocular surface

33
Q

Functions of the mucoaqueous layer

A
  1. TRANSMISSION: Oxygen to corneal epithelium
  2. REGULATION: constant electrolyte levels
  3. SMOOTHENING: ocular surface
  4. MODULATION: epithelial cell function with regulatory factors
  5. REDUCTION of surface tension
  6. CONVERSION of epithelium from hydroPHOBIC–> hydroPHILIC for effective drug delivery
  7. LUBRICATION
34
Q

Components of the aqueous layer

A

Production:
1. Main Lacrimal Gland: aqueous
- located at the lacrimal fossa in the superotemporal orbit
2. Accessory Lacrimal Glands: aqueous
- Krause: 2/3; supero- and inferolateral fornices
- Wolfring: 1/3; proximal margin of tarsus

Composition:
- Na, HCO3: EQUAL to serum
- Urea, Glucose, Lactate, Citrate, Ascorbate, AA: EQUAL to serum
- K, Cl: HIGHER than serum
- Ca, Mg: LESS than serum
- IgA: increased in ocular inflammation; produced by lacrimal glands and substantia propria of conjunctiva
- IgG: increased in ocular inflammation
- IgE, Histamine: increased in ocular allergies (E.g. Vernal KC)
- IgM, IgD

  • electrolyte concentrations important for osmotic flow of fluid
  • tears are HYPERosmotic vs serum: water flows from serum to tears
  • tears are HYPERosmotic vs cornea: dehydrates cornea for clarity

Pathology:
Fuch’s Endothelial Dystrophy
- loss of endothelial cells –> impaired pump mechanism –> leak rate > pump rate –> corneal edema
- give HYPERTONIC saline drops (Muro128)
- increase in the tear osmolarity will drive water from the corneal layers into the tear film –> decreased corneal edema and better vision

35
Q

Clinical correlation of Matrix Metalloproteinase-9 (MMP-9) levels to ocular surface disorders.

A

MMP-9
- Cleaves epithelial BM components and tight junction proteins
- Leads to impaired leaky epithelial barrier and resulting stromal edema
- Levels ~ corneal staining severity ( = late stage DED)
- Elevated in severe Ocular Surface Disorders, Sjogren Syndrome, Dry Eye Disease
- DX: InflammaDry - tests for elevated MMP-9

36
Q

Clinical correlation of Intracellular Adhesion Molecule 1 (ICAM-1) levels to ocular surface disorders.

A

ICAM-1
- upregulated in lymphocytes and vascular endothelial cells when exposed to cytokines
(IL-1, TNF) produced by injury
- facilitates lymphocytic migration via vascular endothelial cells to the lacrimal and conjunctival tissues in DED
- TX: Lifitegrast (Xiidra) - blocks lymphocyte adhesion to ICAM in blood vessels thus preventing tissue migration and maintenance of tear production

37
Q

Components responsible for the antimicrobial properties of tears.

A
  • Lysozyme
  • Lactoferrin
  • Group 2 Phospholipase A2
  • Lipocalins
  • Defensins
  • Interferon: inhibits viral replication
38
Q

Components in the tears which regulate corneal and conjunctival epithelial cell movement?

A

Cytokines (IL-1A, IL-1B, TNF)
Transforming Growth Factor - Beta
Epidermal Growth Factor
Fibroblast Growth Factor

  • Proliferation, migration and differentiation of corneal and conjunctival epithelial cells
  • Regulates wound healing
39
Q

Role of the mucin component in the tear film.

A
  • Coats microvilli of S cells of the corneal epithelium
  • Allows tears to glide easily and evenly across ocular surface
  • Forms a gradient: dilute near the lipid layer and concentrated in the glycocalyx layer near the epithelium
  • 2 types of mucin:
    1. Secreted Mucin: Conjunctival Goblet Cells
  • located in the Crypts of Henle in the area between the subtarsal groove and MCJ
  • MAIN source of the gel-forming mucins
  • MUC5AC: most abundant and studied
  1. Membrane Mucin: bound to corneal and conjunctival epithelium

Examples: MUC1, 4, 16, 5AC, 2

40
Q

What conditions affect the mucin component and cause tear dysfunction?

A

Deficiency:
1. Vit. A deficiency: Bitot Spots (build-up of keratin in the conjunctiva)
2. Conjunctival destruction

Excess:
1. Hyperthyroidism
2. Foreign body stimulation
3. Allergic conjunctivitis

41
Q

Differentials based on mucous discharge.

A

DED: stringy, thin, translucent

Infection: globular, purulent, (+) crusting

Allergic: stretchy, thick, tenacious

Ophthalmology (44 decks)

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