The Cause of Cataracts P.6



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(4) How does the PRESSURE work on the lens?

 

 

3. Collapse of the cells on the lens equator: gBalloon cell formationh

 

<The balloon cell formation>

 

<What mechanism does work on the crush
    by the pressure?>

 

<The shortage of oxygen and insufficiency of ATP>

 

<The shortage of oxygen by some change of the cell
    membrane and the capsule>

 

<The shortage of glucose>

 

<Insufficiency of ATP>

 

<The increase in consumption of ATP>

 

<The decrease of ATP production>

 

<The decrease of the oxygen partial pressure
    in the lens cell>

 

<The pressure gradient occurs by pressure difference. >

 

<How much pressure is put on the cells on the equator?>

 

<The value of real PRESSURE in the unit of mmHg>

 

<Why does the oxygen partial pressure in the cell
     decrease?>

 

<gThe unknown mechanismh>

 

<The oxygen partial pressure in cells on the equator>

 

<Which cell is crushed on the equator?>

 

<People who do not suffer wedge-shaped cataracts>

 

 

 

3.   Collapse of the cells on the lens equator: gBalloon cell formationh

 

  <The balloon cell formation>

This is the first of three types of histopathologic changes in cortical cataracts which David G. Cogan listed.4 (Fig. 2-1, 4-6) This is the first stage of the lens collapse. He describes the state as if epithelial cells grow normally to lens fiber cells on the cell's own way around the equator.  He is aware of unusual changes of cells on the equatorial region. But he describes as follows, gwhy the cells have lost their ability to differentiate into normal fibers in the first place.4h He cannot explain the cause of the change. The sight gballoon cell formationh which Cogan observed is the appearance of dying cells in the equator.

 

Fig.4-6 Balloon cell formation by David G. Cogan4 (The same as Fig.2-1)


Until I began to write this paper, I thought that wedge-shaped cataract started with the simple mechanical crack of the lens cortex. But immediately after I started to write, Cogan's description came out and contradicted our thoughts entirely. Though, I had experiences. For over 20 years, I could stop the progression of wedge-shaped cataracts by proper reading glasses for prevention of the UNREASONABLE POWER in almost all patients. Therefore, I was convinced the balloon cell formation which Cogan showed must be the start of wedge-shaped cataract.

 

<What mechanism does work on the crush by the pressure?>

It is known that epithelial cells lose mitochondria, other cell organelle and nucleus of the cell last in the way of transformation into fiber cells to the deep cortex, in the same way as red corpuscles.11 In this course, the epithelial cell gets gdeformability,h or the gability of a cell to change shape1h and pressure resistance.

I do not know which cell is crushed in the equator. Is it the epithelial cell or the fiber cell? For the time being, we will call the cell gthe cell on the equatorh. Why is the cell on the equator crushed to death? The conceivable mechanisms of this crush by Pressure[a] are the next three items.

A.  A simple mechanical rupture: This rupture does not occur. No one observed this.

 B.  The pressure injures organelle or cell components directly.: It is inconceivable that the organelle or the cell components suffer some mechanical injury from the pressure directly. It is also inconceivable that cell functions stop from the pressure directly.

C.  An accident by an unknown mechanism occurs to the cell other than A and B.: Due to the unknown mechanism from the pressure, the cell is crushed. Because of the mechanism, the cells are crushed on the equator. This unknown mechanism must be the cause.

 

The phenomenon which Cogan showed occurs at the equator. It is the mass death of the cells, obviously. If someone sees that such a phenomenon occurs at the equatorial region, she will think that just the PRESSURE might be the original cause, as I did. I was convinced that the unknown mechanism by the PRESSURE was the principal offender and that it was the root of wedge-shaped cataract.

 

If someone sees that the large-scale death of cells due to the pressure occurs, first he will hit on a shortage of oxygen caused by the pressure. This is because the scale of the death of cells is large and happens at one time. The cells on the equator are sandwiched between the capsule and the cortex. In the cortex, under the sandwiched cells, progressed fiber cells have increased their hardness like the nucleus. Due to the PRESSURE, internal pressure of the sandwiched cell will have increased on the equator. To the human lens, aqueous humor and vitreous fluid are the source of all nourishments, including oxygen and glucose. Therefore, it is thought that owing to the high internal pressure in the cell, permeation of oxygen from the aqueous humor and the vitreous fluid into the cell falls. If oxygen partial pressure falls in the cell, we think the activity of mitochondrion also falls due to the lack of oxygen. As a result, supply of ATP into the cell decreases, and all organs in the cell stop their activities.

Then the cells will begin death with the passing of time. Wedge-shaped cataract begins. This is my hypothesis on the cause of wedge-shaped cataract.

 

<The shortage of oxygen and insufficiency of ATP>

If the supply of ATP decreases in the cell, the cell membrane will be affected first and drastically. J. David Rawn states as follows.

gThe plasma membranes of animal cells maintain an intracellular K(+) concentration of about l40 mM in the presence of an extracellular K(+) concentration of about 5 mM.h gThe pump that maintains this imbalance is the Na(+)-K(+) ATPasean ATP-driven antiport system that pumps two K(+) ions into the cell and ejects three Na(+) ions for every molecule of ATP it hydrolyzes. Each molecule of the Na(+)-K(+) ATPase hydrolyzes about 100 molecules of ATP per second under optimal conditions. About a third of the total energy requirement of the cell is used to drive the Na(+)-K(+) ATPase; in electrically excitable cells, the Na(+)-K(+) ATPase consumes 70% of the cell's energy.12h

If the supply of ATP into the cell decreases, the cell membrane will stop functioning first. Accordingly, the cell accumulates Na(+) ions and then gradually expands. This is the formation of the balloon cell.

 

 I think insufficiency of ATP owing to the shortage of oxygen causes the large-scale death of cells. What change occurs in the cell on the equator due to the PRESSURE?

 

<The shortage of oxygen by some change of the cell membrane and the capsule>

We try to examine whether the cell membrane causes the shortage of oxygen or not.

Molecules of oxygen pass a lipid bilayer of the cell membrane by passive transport. It is inconceivable that the passages in the lipid bilayer of cell membranes are closed by the pressure. It is hard to consider, even if the pressure is 10 or 100 atm.

Lipid bilayer: A structure of the cell membrane. Passive transport: A way by which substances cross through cell membranes without metabolic energy. Atm: A unit of atmospheric pressure, the abbreviated form of atmosphere. 1 atm is 1013 hPa.

It is the same with the capsule. Any change of the cell membrane or the capsule will not cause the shortage of oxygen due to the pressure.

 

<The shortage of glucose>

We try to examine whether a shortage of glucose brings about the insufficiency of ATP or not.

Glucose passes the lens capsule by diffusion. gDiffusionh is another kind of passive transport. Substances pass the membrane via diffusion.

Brian P. Danysh et al. described as follows. gSmaller molecules required for cell metabolism such as glucose, salts, water, O, CO, and the resulting metabolic waste all pass freely through the capsule and into the cortex and nucleus of the avascular lens.13h It is inconceivable that passages in the capsule are closed due to the pressure. Even if the pressure increases to 10 or 100 atm, the structure of the lens capsule will not be compressed so tightly as to close the passageway. The capsule does not prevent the diffusion of glucose. It is the same with the capsule in the equatorial region where zonula insert. In that region, the structure of the capsule is different from other parts.13

Avascular: Not supplied with blood vessels.1h

Glucose passes the cell membrane by facilitated diffusion into the cell. It is also inconceivable that high pressure affects the facilitated diffusion in the cell membrane. This is because high pressure will not affect the lipid bilayer of the cell membrane through compression as with the capsule. It is thought that the shortage of glucose is not caused by high pressure.

Facilitated diffusion: The transportation of substances across the cell membrane by protein molecules.

 

<Insufficiency of ATP>

Furthermore, we try to examine the insufficiency of ATP. There are two causes which can bring about an insufficiency of ATP in the cell. The first is a relative shortage of supply because of an increase in consumption of ATP. The second is a shortage of supply owing to a decrease of ATP production.

 

<The increase in consumption of ATP>

Since an epithelial cell transforms into a fiber cell at the equator, there is the possibility that the increase in consumption of ATP occurs in the cell. However, it is not conceivable. If the shortage of ATP is caused by the increase in consumption, the transformation of epithelial cells into fiber cells simply stops. A relative shortage of supply because of an increase in consumption of ATP does not come about.

 

<The decrease of ATP production>

The possibility left last as the cause of the insufficiency of ATP is a shortage of supply owing to a decrease of ATP production. Two cases are conceivable as the causes of this. The first is direct injuries to mitochondria by the high pressure in the cell. The other is a decrease in the oxygen partial pressure by the high pressure in the cell. About the first, it is inconceivable. This is because deep-sea fish live without any trouble in the sea under hundreds of atm owing to the activity of mitochondria.



<The decrease of the oxygen partial pressure in the lens cell>

The decrease of ATP production must be the cause of the insufficiency of ATP.

The possible origin as the causes of the decrease of ATP production left last of all is the decrease of the oxygen partial pressure in the cell.

Why the oxygen partial pressure in the cell decreases due to the high pressure?

Henry's law cannot be applied to this circumstance. The deep sea under the high pressure is different from this circumstance.

The answer is in the lens equator. The cells on the equator make single layer. Those cells receive the PRESSURE. In the equator, this pressure cannot diffuse sideways or downward. This is most important in thinking about wedge-shaped cataract. On the equator to sideways directions, those cells crowd densely and are surrounded by the same kind of cells. (Fig.4-7) In the downward direction, those cells are on a mass of hardened fiber cells. Consequently, the cells on the equator cannot slide sideways or move downward. Therefore, since the pressure cannot diffuse sideways or downward, all of the pressure presses on the cells sandwiched between the capsule and the mass of hardened fiber cells on the equator. Depending on how a cell is located away from the equator, the pressure which the cell receives gradually becomes weaker. For this reason, the internal pressure of cells on the equator is higher than that of cells removed from the equator. A pressure difference arises here.

 

Fig.4-7 The cells on the equator

 

The pressure difference causes a decrease in oxygen, and the decrease in oxygen causes a decrease of ATP production, then, the cells on the equator die.

<The pressure gradient occurs by pressure difference. >

It is very important that only the internal pressure of cells in the equatorial region is high, whereas the internal pressure of the surrounding cells and the pressure in the aqueous humor are not high. In this equatorial region, a pressure gradient occurs by pressure difference.

The phrase gpressure gradienth we use is different from the gpressure gradienth in hydrodynamics or meteorology. We use the phrase to mean a phenomenon about a semi permeable membrane. When two independent spaces of different pressure sandwich a semi permeable membrane, the pressure gradient occurs between those spaces. This is because the pressure difference is there. The environment of the lens equator will be the same as the artificial semi permeable membrane. The pressure gradient starts to work in the cells on the equator in the same way with the semi permeable membrane.

Semi permeable membrane: A membrane that permits the passage of a solvent, such as water, but prevents the passage of a solvent of the dissolved substance, or solute.1

 

<How much pressure is put on the cells on the equator?>

Again, we see the description by R. F. Fisher. gIn childhood Young's Modulus of elasticity is about 6 x 107 dyn/cm2 and decreases to 3 x 107 dyn/cm2 at 60 and 1.5 x 107 dyn/cm2 in extreme old age.h

The unit gdynh is not used now, gN: newtonh is used.

1 N =105 dyn

No one knows how the power from the elasticity of the capsule changes into the pressure of the capsule onto the lens. However, as the unit of Young's Modulus of elasticity and that of the pressure are the same, the elasticity value should be converted into the quantity of pressure. Therefore, it is supposed that the elasticity value of the capsule can be converted into the pressure value onto the lens by the capsule.

Young's Modulus of elasticity is 3 x 107 dyn/cm2 at the age of 60.

3 x 107 dyn/cm2 = 3 x 102 N/cm2 = 300 N/cm2 

This will be the maximum PRESSURE at that age.

Now we need to know another physical property of the capsule. The capsule has the ability warping outwards because of its elasticity. I quote from a book by Stewart Duke-Elder.

gIt is very resistant to pathological and chemical influencesand is highly elastictending to roll outwards when cutleaving a gaping wound.14h (Fig.4-8)

 

Fig.4-8 The capsule has the ability warping outwards.

 To assume the actual PRESSURE put on the lens, we must think of the power of the capsule in two dimensions. First, we try to fold a fragment of 60-year-old eye's capsule to an angle 70‹. (Fig.4-9) We assume the length of the fragment is about 300 μm. Because the capsule is stretched on the outside, pulling power works on the outside of the angle in the folded state. The pulling powers, named Power A1 and Power A2 respectively, pull the stretched portion of capsule. We think the value of the power will correspond to the value of 3 x 107 dyn/cm2, because the fragment is stretched to a certain degree.

 

Fig.4-9 We try to fold a fragment of capsule to an angle 70‹.

In the equatorial region of the lens, the power of accommodation by the capsule is put on the lens. However, when the lens relaxes as the zonule attached to the angle is pulling the capsule, the pressure on the lens equator will be nearly zero.

In accommodation, each Power A1 and Power A2 pulling on the outside is made by the power of Young's Modulus of elasticity, and each value of the power, or the pressure might be 300 N/cm2. This is because the capsule is not being pulled by ciliary fibers at all in accommodation. It is thought that at that time, the capsule puts the maximum pressure on the cortex. In the most inside part of the folded capsule, since this part isn't stretched, each pulling powers named Power B1 and Power B2 will be always zero N/cm2. I think that as there is a fulcrum on the top of the angle, the power starts at that point. Additionally, we assume that the power named Power C1 summed up Power A1 and Power B1 corresponds really to 1/2 of the number added Power A1 to Power B1.

A1 = A2 = 300 N/cm2,    B1 = B2 = 0 N/cm2

C1 = C2 = (A1 + B1) x 1/2 = (A2 + B2) x 1/2 = 150 N/cm2

We regard Power C1 as the power in the anterior capsule, and Power C2 as the power in the posterior capsule. We assume that the angle of the axis of C1 is 30‹against the longitudinal axis of the lens, and that the angle of the axis of C2 is 40‹against the longitudinal axis. These numbers are rough, approximate values.

The pressure put onto the lens equator, named Power D is,

  D = C1 x cos 30‹+C2 x cos 40‹= 150 x 0.87 +150 x 0.77 = 246 N/cm2

  I think the elasticity of the capsule provokes a pressure of at most 246 N/cm2 in the equator.

 In the posterior pole, where the curve of the lens surface is acute next to the equator, the angle of the axis might be about 80‹against the polar axis. In the same way, although the direction of the pressure is reversed, the pressure put onto the lens in the posterior pole, named power D-polar axis is,

 D-polar axis = C1-p x cos 80‹+C2-p x cos 80‹= 150 x 0.17+150 x 0.17

=51 N/cm2

C1-p and C2-p in the posterior pole correspond to each C1 and C2 in the equator. At the posterior pole, as the capsule is pulled to the maximum extent by zonule in non-accommodation, the capsule puts the maximum pressure on the posterior pole in this state, not in accommodation. I think this pressure is not actually significant at all, and that it is really very small.

 I think that the original or natural shape of the lens without the capsule is near to the shape in relaxation, and that the original or natural shape of the capsule without the cortex and the nucleus is near to the shape in accommodation. The lens without the capsule is, so to speak, a bare lens. Therefore, at a young age, in accommodation the bare lens will pushes the capsule on the equator, at the same time the capsule pushes the bare lens. The pressure in the lens is complicated.



<The value of real PRESSURE in the unit of mmHg>

 We take into consideration the thickness of the capsule. P. Danysh et al. wrote as follows. gThe equatorial region and the anterior pole in both accommodative and non-accommodative lenses are approximately five to ten times thicker than the posterior capsular pole.h gFor instance, the adult human capsule measures between 25 μm and 30 μm at the anterior pole.13h

   The thickness of the capsule is only about 30 μm, and from a microscopic view point, the capsule forms its shape into a gentle, rather than a sharp, curve in the equator. The stretched, outside part of the capsule drawn in Fig.4-9 is not real. The part of the capsule in the equator is stretched actually to a certain length of the segment. If the capsule is stretched any length, possibly the maximum power of Young's Modulus of elasticity might be at work. Therefore, the pulling power might be considerably strong; nevertheless, we attempt to estimate the small pressure. This is because something which weakens the power might work there. Therefore, I assume that the pressure made by the pulling power will truly be from 1/500 to 1/100 of the quantity of 246 N/cm2 shown above.

 The assumed real PRESSURE put on the lens equator is,

246 N/cm2 x from 1/500 to 1/100 

= from 0.49 to 2.46 N/cm2

This is the conceivable value of the real PRESSURE.

 

To assume that the PRESSURE onto the lens cortex is 1/100 of the power provoked by the elasticity, it is 2.46 N/cm2,

as 1 N = 0.10197 kgf,

2.46 N/cm2 = 2.46 x 0.1 kgf/cm2 = 0.25 kgf/cm2

As 1 kgf/cm 2 = 98.0665 kPa,

= 0.25 kgf/cm2 = 0.25 x 98.0665 kPa = 25 kPa

Converting the unit kPa to atm, as 100 kPa = 1 atm,

= 25 kPa = 0.25 atm, approximately.

As 1 atm = 760 mmHg,

  Converting 2.46 N/cm2 into the unit of mmHg,

2.46 N/cm2 = 0.25 atm = 0.25 x 760 mmHg = 190 mmHg

This is the conceivable value of real PRESSURE in the unit of mmHg.

 

To assume that the pressure on the lens cortex is 1/500 of the power provoked by the elasticity, the PRESSURE is 0.49 N/cm2. Converting 0.49 N/cm2 into the unit of mmHg, it is 38 mmHg approximately.

It is conceivable that the capsule puts pressure of from 38 to 190 mmHg onto the cells on the equator.

The assumption of coefficients gfrom 1/100 to 1/500h are the hypotheses, and the value of the power has already been reduced by the angle of the direction of the power. The true number might be about 1/10 or 10/10. I think it is possible.

 Even if the PRESSURE is 30 mmHg, the quantity will be enough to prevent the entrance of oxygen into the cell. In glaucoma, ganglion cells in the retina, or optic nerve cells, die through intraocular pressure slightly over 20 mm Hg. Of course, both the atmospheric pressure and the intraocular pressure also always press the cells on the equator other than the PRESSURE.

 

<Why does the oxygen partial pressure in the cell decrease?>

In the lens equator, if a cell is pressed by the capsule, the pressure difference appears between cells on the equator and surroundings. By the pressure difference, the pressure gradient arises. It is not an osmotic pressure gradient or a concentration gradient. We can regard the cell membrane as a semipermeable membrane. In the semi permeable membrane, by the pressure gradient, gas passes through the membrane from a space of high pressure to another space of low pressure. Molecules of oxygen and others pass the lipid bilayer of the cell membrane by the passive transport. In the cell on the equator, by the pressure gradient, oxygen cannot go into the cell of high pressure from surrounding cells and the aqueous humor. As a result, oxygen partial pressure in the cell decreases.

In this situation, oxygen will not be able to go into the cell of high pressure from surroundings. And at the same time, oxygen will be pushed out from the cell via high pressure.

 

Within the human body, intervertebral disks might have a similar environment, and an eyeball or a vascular system might also have a similar environment. In the eyeball, as intraocular pressure is about 18 mmHg, the pressure in the eyeball is about 18 mmHg higher than other tissue of the body.

Intervertebral disk: A layer of fibrocartilage between the bodies of adjacent vertebrae.1h

In the oxygen cascade, the oxygen partial pressure falls gradually depending on how the tissue is located in the periphery in the oxygen cascade. (Fig.4-10) It is generally explained that the reason for the reduction in oxygen partial pressure is the consumption of oxygen by cells and the tissue. Though, I think it cannot be explained sufficiently by that explanation.

 

Fig.4-10 The oxygen cascade 15

I think, in cells on the equator, the concentration gradient also occurs at the same time. Although gpressure gradienth is gtotal pressure gradienth which contains gpartial pressure,h I think the total pressure and the partial pressure of a gas will work separately.

In the lungs, gas exchange is performed in the pulmonary membrane.

Pulmonary membrane: A membrane which supposedly includes components ranging from a membrane of alveolus to a red corpuscle.

I think in the pulmonary membrane, not only the concentration gradient, but also the pressure gradient of blood pressure occurs. We'll consider the following. In the lens equator, the pressure gradient made by the capsule surpasses the concentration gradient of oxygen. This is because in the lens equator, the pressure difference is rather large and the oxygen concentration difference is rather small. In the case of the lungs, the concentration gradient of oxygen surpasses the pressure gradient made by the blood pressure and the atmospheric pressure. This is because in the lungs, the oxygen concentration difference is rather large and the pressure difference between the blood pressure and the atmospheric pressure is rather small. In this case, of course, the gblood pressureh contains the atmospheric pressure. I think the pressure gradient might affect the fall of oxygen partial pressure.

And I think vascular endothelium might correspond to epithelial cells in the lens. And what happens in a corneal edema in glaucoma? Death of nerve cells of a retina in glaucoma? These are not our tasks.

In the equator, by the pressure gradient, the oxygen partial pressure in the cell decreases.

 

< gThe unknown mechanismh>

If the internal pressure of a cell on the equator increases, the oxygen partial pressure in the cell falls. Accordingly, oxygen in the cell will run short. Subsequently, the activity of mitochondria declines first. Because of this, the ATP required to maintain the activity of the cell is not supplied to the cell. Consequently, the cell membrane stops to function. The cell then accumulates Na(+) ions, and the cell gradually expands. Next, the cell organella stops to function and the cell itself dies. The destruction of the lens begins. This cell death is the beginning of a wedge-shaped cataract. This is the phenomenon David G. Cogan wrote about. And this is exactly the unknown mechanism we chased.

 

<The oxygen partial pressure in cells on the equator>

A human lens is floating in an aqueous humor in an aqueous chamber. The aqueous humor is located behind of the tissues in the oxygen cascade. Oxygen in the aqueous humor comes from a ciliary body, an iris, and partly from a vitreous body.

The aqueous humor depends on them for the supply of all nourish, including oxygen. The cells of a corneal endothelium die occasionally, through insufficient oxygen. It occurs often in a contact lens user. Those cells cannot survive through oxygen from the aqueous humor alone, and they depend on oxygen infiltrated from the surface of the cornea. Ying-Bo Shui said as follows, in rabbit eyes, goxygen levels were highest near the surface of the pars plana of the ciliary body (21 mm Hg) and beneath middle of the iris (23 mm Hg). Near the pars plicata of the ciliary body, oxygen levels were only 16 mm Hg. As the aqueous humor moved beyond the midpoint of the iris, oxygen levels decreased to below 20 mm Hg.16h

There is a possibility that the oxygen partial pressure in the aqueous humor near the corneal endothelium is very low. It might be about 10 mm Hg. If so, the human cell might not be able to survive an oxygen partial pressure under about 10 mm Hg.

I think that the oxygen partial pressure in cells on the equator in non-accommodation is about 15 mm Hg or less, and that the pressure in accommodation might be below 1 mm Hg.

 

<Which cell is crushed on the equator?>

It is conceivable that the pressure resistance of an epithelial cell is originally not so high, and that the pressure resistance of a fiber cell is not so high on the equator. The epithelial cell moves under the capsule from the anterior polar region towards the equator by degrees, while it repeats cell divisions. It is conceivable that around the equator, the epithelial cell begins to transform into a fiber cell. During the transformation, the cell moves further inward towards the lens nucleus. On the course of transformation, while the cell loses its mitochondria, the fiber cell gains pressure resistance gradually.

It is conceivable that, at the beginning of the transformation, the fiber cell begins to gain pressure resistance. Even if it is low, it might be far higher than that of an epithelial cell. I assume that an epithelial cell starts to require a low quantity of ATP during the early stage of transformation, and that the cell membrane also starts to require the activity of Na(+)-K(+) ATPase less often. Finally, the fiber cell in the lens nucleus must require ATP less often, while oxygen and glucose will hardly be able to reach the lens nucleus.

It is conceivable that a cell which is crushed on the equator is an epithelial cell. This is because it must require a large quantity of ATP.

We can determine the cell crushed on the equator is the epithelial cell.

 

<People who do not suffer wedge-shaped cataracts>

From our clinical experience, people who suffer from wedge-shaped cataracts are in the minority. It is thought that in the major of people, the cells are not crushed at the equator in spite of the high PRESSURE. I think that in these people at the age of presbyopia, either epithelial cells begin, or have already transformed into fiber cells at the equator. Accordingly, as the cells do not require much ATP, they are not crushed at the equator. They do not suffer wedge-shaped cataracts.





The Cause of Cataracts P.6