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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
Anaerobic glycolysis
Aerobic glycolysis
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+)
Note 
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