Ocular Phys and BioChem: Lens

Development of lens

1. Surface Ectoderm

2. Lens Placode (induced by optic vesicle to become-->

3. Lens pit

4. Lens vesicle

5. Posterior epithelium elongates anterior --> primary lens fibers --> embryonic nucleus

Anatomy of the adult lens

Anterior - epithelial cells

Posterior - NO epithelial cells

lens capsule - basement membrane

anterior lens epithelium (start at pole and migrate to equator and develop into fibers)

Cortex

Adult

infantile

Fetal

Embryonic

Cortex of lens

outer 1/3

Nucleus of lens

inner 2/3

Function of the lens

Major refractive component

Metabolically maintains transparency and clarity

filters UV light

Facilitates accommodation via relationship with w ciliary muscle

Major refractive component

+15 to +20D

Metabolically maintains transparency and clarity by

regular arrangement of fibers

avascular

no innervation

high concentration of tightly packed crystalline proteins

Regulation of H2O and electrolyte balance

The lens has a low _____ content and a high ____ content

water

protein

optimal optical function of the lens

The lens has a _____ index of refraction than the aqueous

higher

the lens remains hydrated enough to

change shape during accommodation

Lens capsule

hypertrophied (thickened) basement membrane produced by anterior lens epithelial cells and posterior lens fibers

acellular transparant and elastic (No elastic tissue)

Lens epithelium zones

central

intermediate/Germative/Proliferative

transition/Equatorial

____ is the main location of lens metabolism

lens epithelium

Why?

epithelial cells contain nuclei, smooth and rough ER, mitochondria, ribosomes

(remember the lens fibers lack organelles!)

contains 1/2 of membrane ATPase pumps (superficial structure so it can bring in things we need for metabolism)

teamwork = low resistant gap junctions between adjacent epithelial cells and lens fibers

Lens energy is almost entirely dependent on ______ for metabolism

glucose

not O2 (its avascular)

Primary source of glucose is the

aqueous

pulled in by facilitative diffusion via insulin dependent glucose transporter

Glucose metabolism generates

ATP

ATP is used for

making stuff: mitosis, protein synthesis

move stuff: membrane pumps

maintain stuff: lens hydration, fight free radicals

2 possible ways to generate ATP

Anaerobic Glycolysis

Aerobic pathway: Glycolysis + TCA/Kreb's cycle + ETC

2 pathways that metabolize glucose but dont make ATP

Pentose phosphate pathway

sorbitol pathway

Anaerobic Glycolysis

most common pathway for glucose metabolism

Anaerobic glycolysis location

the cytoplasm of the lens epithelial cells and superficial fibers

NOT the lens nucleus

Anerobic Glycolysis rate limiting step

hexokinase

hexokinase

decreases with age

why we see aging changes in lens

aerobic pathway (krebs cycle)

low use (< 5%) but accounts for 20% of all ATP generates

low amount of glucose for a lot of ATP

aerobic pathway (Krebs cycle) limiting factors

aerobic process (lens has low O2)

limited to mitochondria of epithelial cells

Pentose Phosphate Pathway is used

not in all tissue

liver, RBCs, adrenal cortex, mammary glands, and lens

Pentose Phosphate Pathway generates

NADPH and Ribose

NADPH is needed for

1. Coenzyme for sorbitol pathway

2. Formation of Glutathione

3. Lipid and nucleotide synthesis

Glutathione

reduces protein aggregation = lens transparency

helps maintain integrity of ATPase pumps

antioxidant --> transparency

Ribose is needed for

nucleic acid synthesis

cell mitosis

Sorbitol pathway is activated with

low levels of hexokinase or high levels of glucose (diabetes or low hexokinase)

Glucose --()--> sorbitol --()--> fructose

aldose reductase

sorbitol reductase

some tissue only have aldose reductase and low/ no sorbitol which causes

sorbitol to accumulate

Sorbitol attracts

water

increases oxidative stress

Build up of sorbitol in the lens

cataract

Build up of sorbitol in the retina

retinopathy

Build up of sorbitol in the kidney

nephropathy

Build up of sorbitol in the schwann cells

neuropathy

Lens Y sutures are located in the

fetal nucleus

LENS PROTEINS

There are higher concentration of amino acids in the

lens compared to the aqueous

The concentration of amino acids rely on

on active transport

Requires ATP

(we are going against the concentration gradient)

use Na+k- ATPase pumps

Protein syntheis location

lens epithelium and outer cell layers

stops after lens fiber formation

protein synthesis is an ____ process

energy intensive

requires ATP

Two groups of lens proteins

water soluble

water insoluble

Water soluble proteins

Crystalline Proteins

90%

located in lens cortex

alpha, beta, gamma

Alpha crystalline proteins

largest molecules

chaperones molecules - stabilize beta/gamma to prevent chemical changes or aggregation (transparancy)

Beta crystalline proteins

most abundant

Gamma crystalline proteins

smallest, least abundant, least soluble, susceptible to O2 damage

Water insoluble protein

10%

cytoskeletal pr

Lens fiber cells

epithelial cells differentiate into lens fiber cells at equatorial region

the apex of cells move

the basal portion moves

anteriorly

posteriorly

nuclei of fiber cells move

anteriorly and form lens bow

Lens lipids role

membrane structure

Examples of lens lipids

Phospholipids

cholesterol

Where is metabolism in the lens

lens epithelial cells

primary source of energy for the lens is

glucose from the aqueous

Aerobic pathway takes place in

mitochondria in lens epithelium

anaerobic pathway takes place in

cytoplasm of lens epithelium

Which pathways do not produce ATP

Pentose Phosphate Pathway

Sorbitol Pathway

What pathway is most often used in glucose metabolism in the lens

anaerobic

low O2 in the lens!

Which produces most ATP from 1 molecule of glucose

Aerobic

Sorbitol buildup leads to

swelling

What is the most abundant protein in the lens

Crystalline (water soluable)

H2O and electrolyte balance

active ion pumps!

requirements:

intact membrane

ATP (90% of ATP generated in lens)

Ion pumps are located

in lens epithelial cells and posterior lens fiber

Na+/K+ ATPase pump

transports 3 Na+ out of lens for every 2 K+ moved in

Pump leak system

Na comes back in passively

Calcium pumps

located on posterior lens and lens epithelium

if the ion pumps fail

increased intracellular calcium

decreases na/k ATPase activity

lens swelling

decreased protein synthesis

increased protein aggregation

_______ allows the flow of ions and water between adjacent rings throughout the lens

gap junctions

because if the Na/K ATPase pumps tge unterior of the lens is more

negative

There are UV filter compounds found in the lens with higher concentration in the

nucleus than the cortex

Increased UV damage with age because of

- modification of crystalline proteins

- increased oxidative stress

- increased chromophore concentration = brunescense

Oxidation

loss of electrons

Reduction

gain of electrons

Pro oxidants

reactive oxygen species

Antioxidants

Glutathione

Vitamin C

Catalase

Vitamin E

Carotenoids

Free radicals

natural byproduct of metabolism or UV exposure

free radicals down regulate

Na/K ATPase = lens swelling and apacification

Free radicals from H2O2 can cause

dysfunction to hexokinse and impair glycolysis

decreases ATP

messes up pumps

Free radicals form

protein aggregates

The principal antioxidant in the lens is

Glutathione

Glutathione

reduces free radicals and oxidative stress

detoxifies H2O2

from aqueous or generated by lens epithelium

Ascorbic Acid (Vitamin C)

concentrated in lens epithelium and cortex

scavenges free radicals

Catalase

concentrated ni lens epithelium

Converts H202 --> H20 in high concentration of peroxide only

Diabetic cataracts: duration of disease

longer diabetes = worse

DM cataracts: metabolic control

poor = worse

DM Cataracts: age

older people more likely to develop

diabetic pts get cataracts sooner than non diabetics

less hexokinase w age!

Diabetic Cataracts physiology

low levels of hexokinase or high glucose

sorbitol buildup

(will read more minus) on refraction

Diabetic signs and symptoms

Blur

Glare

Change in RE

Posterior Sub-capsular Cataract

underneath capsule

close to nodal point

Nuclear cataract Pathophysiology

decline in Glutathione

increase ROS damage

more aggregation --> yellow

accumulation of chromophores -->yellow

Nuclear Cataracts signs and symptoms

gradual, general blur

things seem dimmer

change in refractive error (myopic shift)

Cortical cataract pathophysiology

increased membrane permeability and ion transport

Ionic imbalance leading to disruption of fibers

Cortical Cataract: Signs and Symptoms

blur worse at night

glare that gets worse at night

hyperopic shift (thicker at edges)

Subcapsular Cataract: Pathophysiology

Epithelial-like cells that do not elongate properly migrate from the equatorial region to the posterior pole

UV or radiation damage

steroid use!

Subcapsular Cataract signs and symptoms

very sudden vision changes (close to nodal point)

blur worse at near

increased difficulty reading

blur worse in brighter settings