9 Corneal edema and metabolism

Two regions of cornea typically affected simultaneously by increased water content:

stromal and epithelial edema

T or F, stromal and epithelial edema always occur together

F, can occur independently

Which curvature is typically affected in corneal edema, anterior or posterior?

posterior

Why is anterior curvature of cornea resistant to edema?

has interweaving of lamellae

Bullous Keratopathy

permanent corneal edema from failure in endothelial pump function or damage to endothelial cells

Causes of bullous keratopathy

• endothelial dystrophy (Fuch’s)

• injury

• surgery

• hypoxia

In bullous keratopathy, there is excess fluid in __, decreased visual acuity, loss of contrast, glare, and photophobia

epithelium and stroma

Forces ergulating corneal hydration

IP, SP, IOP, endoehtlium pump, tear evao/osmosis (minor)

What does negative imbibition pressure do?

Draws fluid into cornea (can take in more water)

What does positive imbibition pressure do?

water leaves stroma

What is the main factor that generates imbibition pressure?

negatively charged GAGs

Normal value of imbibition pressure

-40 mmHg

As water content (increases or decreases), IP increases towards zero

increases

Is imbibition pressure helped by or counteracted by endothelial pump?

counteracted by

Does IOP affect IP?

yes

Normal swelling pressure value with 78% water content

55 mmHg

As water content increases, SP __

decreases

What factors cause SP?

negative GAGs repelling each other, don’t want to compress

As cornea swells, GAGs are (closer or further), reduces repulsive force in SP

further

IOP normal value

15 mmHg

What is the hydraulic force pushing on the cornea and (from anterior chamber) through leaky TJs into stroma?

IOP

What forces are generated by GAGs?

IP, SP (NOT IOP)

IP =

IOP - SP

normal values into the IP=IOP-SP

-40=15-55

When endothelial pump is decreased, IP will

(less water in cornea, IP will) increase

When endothelial pump is decreased, SP will

decrease

When tear evaporation increases, what happens to water in cornea?

draws water from cornea

Less evaporation can __ water content

increase (edema)

In bullous keratopathy, how do IP, IOP, and SP change?

more water (edema) → IP increases, SP decreases (both closer to 0), IOP does not change

If IOP is extremely high (exceeds SP), what happens to water? Is IP positive or negative?

water is pushed out of stroma (like sponge), ONLY have epithelial edema, not stromal!

IP is positive (pushes water out)

If IOP is elevated (but not >SP),

pump function cannot keep up with water infiltration → edema?

In phthisis bulbi (pump function is lost with hypotony), IOP = __? Epithelial and/or stromal edema?

zero (puncture hole); stromal edema only

What is the relationship between IP and SP in phthisis bulbi?

They equal each other because IOP = 0

When can you get stromal edema only?

phthisis bulbi/hypotony/endothelial pump loss (IOP = 0)

When can you get epithelial edema only?

IOP > SP

What could cause reduction in pump function → edema?

hypoxia, pH reduction

How does hypoxia cause corneal edema?

increase in anaerobic metabolism of corneal pump → build up of lactate → osmotic draw of water

How does low pH result in edema?

inhibits pump function and reduces ion transport efficiency

Anaerobic glycolysis converts __ to __ through what enzyme?

pyruvate to lactate; lactate dehydrogenase

lactate dehydrogenase

converts pyruvate to lactate in anaerobic glycolysis

T or F, glycolysis requires oxygen

F

2 reasons sleep causes corneal swelling

hypotonic tears (less evaporation) and hypoxic metabolism of corneal tissues (→ more lactate)

How does Fuch’s endothelial corneal dystrophy lead to edema and opacification?

1) guttata formation

2) loss of endothelial cells (which usually supports pump function)

3) edema severity increases

4) opacification of cornea, pain, vascularization of cornea

T or F, Descemet’s membrane damage (like by guttata) can lead to bullous keratopathy

T

Describe Descemet’s membrane layers

Posterior non banded layer (PNBL), (anterior) banded layer

Main collagen type of PNBL

IV

Main collagen type in banded layer of descemet’s

VIII

Which layer of DM increases with age?

PNBL

Which layer of DM is formed during embryonic/fetal development?

Banded

What can a mutation in COL8A2 (encodes collagen VIII) cause?

FECD → thicker DM → abnormal accumulation of collagen VIII

How does cornea get energy while being avascular?

• glucose diffuses from the aqueous humor

• oxygen diffusion from aq humor

• Hexose Monophosphate Shunt?

What allows glucose to pass through plasma membrane of corneal endothelium and epithelium?

GLUT transporter

are GLUT transporters uni or bi-directional?

bi-directional

85% of corneal glucose is used in

anaerobic glycolysis (no oxygen or mitochondria)

3 ways glucose is used in cornea

1. Anaerobic glycolysis

2. Aerobic glycolysis

3. Hexose-Monophosphate Shunt (HMS)

What determines the metabolic pathways that use glucose?

• oxygen concentrations

• number of mitochondria

• active enzymes available

T or F, the oxygen concentration is greater in the endothelium/posterior stroma than the epithelium/anterior?

F, gradient is opposite of glucose

Where are there more mitochondria in the cornea?

the endothelium (opposite of where oxygen is present)

Which uses more oxygen, epithelium or endothelium of cornea?

endothelium

Explain why there is more oxygen towards epithelium

endothelium using oxygen, concentration gradient → oxygen diffuses down

Glycolysis produces ___

pyruvate

What happens to pyruvate from glycolysis?

• aerobic → TCA → Oxidative phosphorylation → CO2 + H2O + NAD+

• or anaerobic → lactate (+ 2 NAD+)

What metabolism predominates in cornea?

anaerobic metabolism

Where do ROS come from?

mitochondrial metabolism (aerobic)

What do ascorbic acid and ALDH3A1 (aldehyde dehydrogenase) do?

donates electrons to ROS

What is the glutathione pathway?

How ascorbic acid and ALDH3A1 regain electrons

The glutathione pathway needs NADPH or NADP+?

NADPH

Anterior keratocytes are more or less aerobic than posterior?

more aerobic (more oxygen is available anteriorly because endothelial mitochondria uses the oxygen posteriorly)

Most aerobic tissue in cornea (keep in mind all cornea is predominantly anaerobic)

corneal endothelial cells

What is produced by HMS that limits ROS generated by aerobic glycolysis?

NADPH, goes through glutathione pathway

What utilizes the HMS?

corneal epithelium

Two main functions of HMS

• produce NADPH → used in lipid synthesis and glutathione pathway

• produce ribose-phosphate for RNA and DNA synthesis

What is G6PD deficiency?

Inherited glucose-6-phosphate dehydrogenase deficiency, makes people (400 million) prone to oxidative damage → pterygium and cataracts

Favism

hemolytic anemia due to ingestion of fava beans → hydrogen peroxide production

lactate diffuses from __ to _

corneal stroma to aqueous humor

What transporters facilitate lactate transport transcellularly into aq humor?

Monocarboxylate cotransporters (MCTs)

Lactate cannot pass epithelial barrier into tear film, so any excess lactate is

transported out of cells and diffuses posteriorly

What do the apical and basolateral MCT do?

• Basolateral transporters move lactate from stroma into endothelial cells

• Apical transporters from endothelial cells into aq humor

What determines the metabolism of keratocytes, and what GAGs they produce?

NAD+ : NADPH ratio

The reaction of pyruvate to lactate occurs more readily in posterior cornea because

lower O2 availability

The production of what GAG is favored in the posterior stroma?

Keratan

Why is Keratan made more in posterior stroma?

More NAD+ (from lactate production from anaerobic metabolism) inhibits enzyme required for Dermatan

What GAG is made more by keratocytes in the anterior stroma?

dermatan (more O2, more aerobic metabolism, less lactate, less NAD+)