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271 lines
21 KiB
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<head><title>Leakiness, aging, and cancer</title></head>
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<h1>
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Leakiness, aging, and cancer
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</h1>
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A thin layer of fibrin lining blood vessels provides a filtering barrier that helps to strengthen the wall and
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prevent other proteins from leaking out of the vessels, and it participates in repair processes when the blood
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vessel is broken.<p>
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Cellular energy metabolism is the basis for maintaining the barrier functions. Energy depletion causes the
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endothelial cells lining blood vessels to become excessively permeable.
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</p>
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<p>
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When the organism's resistance is low, proteins and fats that normally remain inside the bloodstream can
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escape into the extracellular matrix and enter cells, contributing to their stress and disorganization, and
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other materials can escape from cells and enter the bloodstream.
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</p>
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<p>
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One of the simplest demonstrations of fibrin leakage is to shine a beam of light into the eye; the presence
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of fibrin and other inappropriate molecules diffuses the light, causing a "flare" in the aqueous
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compartment. Albumin, a small protein from the blood, is often seen in the urine during stress. The effects
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of that sort of leakage vary with each organ.
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</p>
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<p>
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Fibrin is an essential structural and functional part of the organism, but when it escapes from the
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bloodstream it participates in the degenerative processes of inflammation, fibrosis, and tumor formation.
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(Its fragments stimulate secretion of inflammatory mediators: Hamaguchi et al., 1991.)
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</p>
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<p>
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In the hormonal environment dominated by estrogen, mild stresses such as exertion, or even restless sleep,
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allow toxins (and sometimes bacteria) from the intestine to enter the bloodstream, triggering a complex
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chain of events that create a systemic inflammatory state. Although these processes have been observed in
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many simple experiments, their implications are almost always neglected or denied or explained away.
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Incorporation of certain polyunsaturated fats into the tissues increases the leakiness of blood vessels, and
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amplifies the reactions to stresses and inflammatory stimuli.
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</p>
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<p>
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Antioxidants, thyroid hormone, progesterone, and antiinflammatory agents, including glycine or gelatin,
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niacin, and saturated fats, can prevent, and in many cases reverse, these degenerative inflammatory
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processes.
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</p>
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<p>
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Even a single celled organism has to keep its parts separate, and highly differentiated multicelled
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organisms have many special systems that serve to keep their parts separate, so the different tissues and
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organs can maintain their distinct functions.
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</p>
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<p>
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The movement of substances from blood to cell, and from cell to cell, is normally very tightly controlled,
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and when the systems that control those movements of water and its solutes are damaged, the tissues'
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structures and functions are altered. The prevention of inappropriate leakiness can protect against the
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degenerative processes, and against aging itself, which is, among other things, a state of generalized
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leakiness.
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</p>
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<p>
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When cells' energy is depleted, water and various dissolved molecules are allowed to move into the cells,
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out of the cells, and through or around cells inappropriately. The weakened cells can even permit whole
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bacteria and similar particles to pass into and out of the blood stream more easily.
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</p>
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<p>
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One of the earliest investigators of the effects of stress and fatigue on nerves and other cells was A.P.
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Nasonov, in the first half of the 20th century. A.S. Troshin (1956) has reviewed his work in detail. He
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showed that in cells as different as algae and nerve cells, fatigue caused them to take up dyes, and that
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the dyes were extruded, if the cells were able to recover their energy. When nerve cells are excited for a
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fraction of a second, they take up sodium and calcium, but quickly eliminate them. Prolonged excitation,
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leading to fatigue, can gradually shift the balance, allowing more substances to enter, and to stay longer.
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</p>
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<p>
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When nerves or other cells are quickly killed with heavy metals such as osmium, the metals are visible in a
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layer at the surface, which is sometimes taken as evidence of a "cytoplasmic membrane," but if the cells
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have suffered oxygen deprivation or have been injured by X-rays, the metal will be visible as a grey color
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evenly distributed through the cell. The deposition of the metal occurs when it reacts with electrons. In
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the relatively vital cell, the heavy metal stops at the surface, and is mostly reduced there, but the
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devitalized cell presents no structural or chemical barrier to the entry of the metal, and the reactive
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electrons appear to be evenly distributed through the cell. Oxygen deprivation, X-irradiation, and other
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stresses cause the cell to be unable to use electrons to produce energy, and instead the electrons are
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available to react destructively with whatever may be available. While Nasonov showed that dyes and even
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particles enter energetically depleted cells, newer techniques are able to show that the leaky cells are
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structurally disrupted by the excessive reduction of their proteins, by excited electrons and free radicals.
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</p>
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<p>
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In the 1970s, experimenters found that muscles from vitamin E deficient animals released their enzymes when
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washed in a saline solution, more easily than did the muscles from vitamin E replete animals. Other
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experiments around the same time showed that reducing the ATP of muscles caused a similar loss of their
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ability to retain their proteins.
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</p>
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<p>
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Over the years, many experiments have established, both in vitro and in vivo, that fatigue, stress, aging,
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and inflammation cause cells to lose their normal constituents, but also to allow foreign materials to enter
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more easily.
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</p>
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<p>
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When I was working on my thesis, around 1970, investigating the effects of aging on the metabolism of the
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uterus, I found that the changes occuring during aging were (in all the ways I tested) the same as those
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produced by X-irradiation, excess estrogen, oxygen deprivation, excess polyunsaturated fats, and vitamin E
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deficiency.
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</p>
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<p>
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Although everyone working in the lab was familiar with the appearance of the uterus from old hamsters (they
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are typically large, stiff, and bluish), everyone was surprised when I suggested that the aged uteri seemed
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to function as if they were under the influence of a considerable amount of estrogen. Everyone was familiar
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with the medical textbook doctrine that "menopause is caused by estrogen deficiency." In humans,
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gynecologists know about "Chadwick's sign," the fact that the uterine cervix turns blue or purple during
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pregnancy, and everyone knows that blood is blue when it's deprived of oxygen, so it's surprising that
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estrogen's effect on tissue oxygenation isn't widely recognized.
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</p>
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<p>
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When estrogen is given to an animal, it almost instantly causes capillaries to become leaky, allowing water
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to move out of the blood stream, and at the same time, estrogen causes cells to take up water. Both of these
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processes are the same as the early effects of oxygen deprivation. In the normal reproductive cycle, the
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surge of estrogen lasts only a few hours, and normal permeability is quickly restored by increasing
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progesterone. During those intermittent short exposures to estrogen, there isn't a massive leakage of serum
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proteins into the tissues. During the time of estrogenic influence, all kinds of cells are influenced, with
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the excitatory equilibrium of nerve cells, glandular cells, and immune system cells being shifted, lowering
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the threshold of excitation, or prolonging the excited state.
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</p>
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<p>
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Anything that causes inflammation causes a similar loss of water from the blood, as it is taken up by
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swelling cells. If inflammation is generalized, it causes circulatory shock, because the volume of the blood
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has become insufficient to serve the organism's needs. One of Hans Selye's earliest observations of the
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effect of an overdose of estrogen was that it causes shock.
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</p>
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<p>
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Although water loss causes the blood to become more viscous under the influence of estrogen, the plasma
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becomes hypotonic, meaning that it contains fewer osmotically active solutes than normal; some of the sodium
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that helps to maintain the blood's osmotic balance is lost through the kidneys, and some is taken up by the
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red blood cells and other cells. The osmotic imbalance of the blood causes tissue cells to take up more
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water, contributing to their increased excitability. In many cases, the vascular leakage of inflammation and
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shock can be corrected by using osmotically active substances, such as starch solutions, gelatin, or
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concentrated sodium chloride.
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</p>
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<p>
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The tissue water retention caused by estrogen, hypoxia, and stress is analogous to the swelling of gels and
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colloids, that is, it's governed by the state of the electrons and counterions in the system. Excitation,
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fatigue, or injury can cause a shift of pH toward alkalinity, causing water uptake and swelling.
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</p>
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<p>
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The blue color of the pregnant cervix, or of the uterus in an animal given an overdose of estrogen,
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indicates that the tissue isn't sufficiently oxygenated to maintain its normal red color, even though the
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flow of blood is increased. Some experimenters have noticed that newborn animals sometimes have the postural
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reflex (lordosis) that indicates an estrogenic state, and that suffocation can produce the same reflex.
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Irradiating animals with x-rays will also produce the whole range of estrogenic effects.
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</p>
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<p>
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One of the features of the aged uterus that I studied was the age pigment, lipofuscin, a brown waxy material
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that accumulates in old or stressed tissues. Prolonged dosage with estrogen accelerates the formation of
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this pigment, which is largely derived from oxidized polyunsaturated fatty acids. Increased amounts of those
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fats in the diet, or a deficiency of vitamin E, or exposure to ionizing radiation, or oxygen deprivation,
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can also accelerate the formation of the age pigment. The presence of the pigment intensifies the effect of
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estrogen, since the pigment wastes oxygen by functioning as an oxidase enzyme.
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</p>
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<p>
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Other tests that I did on aged, or estrogenized, uterine tissue indicated that several oxidative systems
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were activated; for example, the tissues showed an extremely high activity of the enzyme peroxidase, and a
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very intense reduction of a chemical dye (tetrazolium/formazan) that indicates the presence of reductive and
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oxidative activity, of the sorts caused by radiation and oxygen deprivation. These reductive and oxidative
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processes include the production of some free radicals that are capable of reacting randomly with
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polyunsaturated fatty acids.
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</p>
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<p>
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The interactions between estrogen and the polyunsaturated fats are now coming to be more widely recognized
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as important factors in the inflammatory/hyperpermeable conditions that contribute to the development of
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heart and blood vessel disease, hypertension, cancer, autoimmune diseases, dementia, and other less common
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degenerative conditions.
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</p>
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<p>
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Estrogen increases lipid peroxidation, and maintains a chronically high circulating level of free fatty
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acids, mainly PUFA, activates the phospholipases that release arachidonic acid from cells leading to
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formation of prostaglandins and isoprostanes, and increases the enzymes that form the inflammation-promoting
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platelet activating factor (PAF) while suppressing the enzymes that destroy it, and increases a broad range
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of other inflammatory mediators, interleukins, and NF-kappa B.
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</p>
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<p>
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The leakage of enzymes out of cells and into the blood stream is recognized medically as evidence of damage
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to the organ that is losing them. Different combinations of enzymes are commonly considered to be evidence
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of a heart attack, or skeletal muscle damage, or liver disease, pancreatitis, prostate cancer, etc. But
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often the reason for the leakage isn't understood. Hypothyroidism, for example, causes leakage of enzymes,
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possibly mainly from the liver, but also from other organs. Excess estrogen, intense exercise, starvation,
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anything that increases lipid peroxidation and free radical production, such as drinking alcohol when the
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tissues contain polyunsaturated fats, can cause organs such as heart and liver to leak their components.
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</p>
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<p>
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The loss of enzymes increases the energy needed to stay alive, but it doesn't necessarily change the basic
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functions of the cell. (Though when mitochondrial enzymes leak out into the cytoplasm, the cell's energy
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metabolism is impaired, at least temporarily.) But the entry of catalytic materials from other tissues
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changes the organization of a cell, giving it conflicting instructions. In many situations, as L.V.
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Polezhaev and V. Filatov demonstrated, the substances released during stress and degeneration serve to
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stimulate healing and regeneration. But when the resources aren't available for full repair or regeneration,
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only a scar, or atrophic fibrosis, or a tumor will be formed.
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</p>
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<p>
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In severe stress, intracellular fibrin deposits have been found in the heart and other organs, including the
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prostate gland. Deficiency of testosterone causes vascular leakage into the prostate. Fibrin promotes tumor
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growth, partly by serving as a matrix, partly by releasing stimulatory peptides.
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</p>
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<p>
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Kidney disease, diabetes, pregnancy toxemia and retinal degeneration are probably the best known problems
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involving vascular leakage, but increasingly, cancer and heart disease are being recognized as consequences
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of prolonged permeability defects. Congestive heart failure and pulmonary hypertension commonly cause
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leakage of fluid into the lungs, and shock of any sort causes the lung to get "wet," a waterlogged condition
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called "shock lung." Simply hyperventilating for a couple of minutes will increase leakage from the blood
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into the lungs; hyperventilation decreases carbon dioxide, and increases serotonin and histamine. Hyperoxia
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itself contributes to lung injury, and exacerbates emphysema, though it is common to see patients breathing
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a high concentration of oxygen. Emphysema (which can be caused by hypothyroidism or hyper-estrogenism, and
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often can be cured by thyroid or progesterone) and many other respiratory problems are associated with
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capillary leakage. Cells of the lung and intestine are able to synthesize their own fibrin, apparently
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because of their special problems in preventing leakage. Prolonged systemic inflammation can lead to lung
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fibrosis, and fibrosis increases the likelihood of lung cancer.
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</p>
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<p>
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The inflammatory state that causes exaggerated cellular permeability is very closely related to
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"hyperventilation," the loss of too much carbon dioxide. The release of serotonin during hyperventilation
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isn't the only cause of vascular leakage; the carbon dioxide itself is an essential factor in regulating the
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state of cellular electrons and in maintaining cellular integrity. Hyperventilation, like the shift from
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oxidative to glycolytic energy production that typifies estrogenized or stressed cells or cancer, raises
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intracellular pH. In the case of mast cells, increasing alkalinity causes them to release histamine
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(Alfonso, et al., 2005), but similar "alkaline-induced exocytosis" seems to occur in all stressed tissues.
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</p>
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<p>
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The blood platelets that become incontinent and leak serotonin in the absence of carbon dioxide are
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undergoing the same structural stresses experience by endothelial cells, smooth muscle cells, mast cells and
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all other cells when carbon dioxide is depleted. Although it has been about 70 years since Yandell Henderson
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made it clear that supplemental oxygen should be combined with carbon dioxide, mechanical ventilation in
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hospitals is still causing lung injury resulting from hyperventilation, i.e., the absence of carbon dioxide.
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A similar misunderstanding of biology was involved in the use of dialysis to treat kidney disease. Until
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recently, commercial dialysis fluids contained acetate and/or racemic lactate instead of bicarbonate,
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because of the difficulty of preparing bicarbonate solutions, and the result was that very prolonged
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dialysis would damage the brain and other organs. (Veech and Gitomer, 1988, Veech and Fowler, 1987.)
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Dialysis has been seen to increase lung permeability Bell, et al., 1988).
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</p>
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<p>
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Amyloidosis produced by chronic dialysis affects all organs, but its effects are best known in the brain,
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heart, kidneys, and lungs. Serum amyloid-A is one of the acute phase proteins, like C-reactive protein
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(CRP), that are produced by inflammation. Estrogen, radiation and other stresses increase those
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pro-inflammatory acute phase proteins, and decrease protective albumin, which is called a "negative acute
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phase protein," since it decreases when the other acute phase proteins increase. The liver is the major
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source of the acute phase proteins, and it is constantly burdened by toxins absorbed from the bowel;
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disinfection of the bowel is known to accelerate recovery from stress.
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</p>
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<p>
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Seen from the perspective of the stress-leakage syndrome, any serious injury or sickness damages all organs.
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The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of
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inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress
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can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown
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products--aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide,
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nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses. Both proline and
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glycine (which are major amino acids in gelatin) are very protective for the liver, increasing albumin, and
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stopping oxidative damage.
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</p>
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<p>
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Saturated fats are protective against free radical damage and can reverse liver fibrosis. Thyroid hormone
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protects against excess estrogen, and can prevent or reverse fibrosis of the heart. Antiestrogens are widely
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effective against vascular leakage. Thyroid, progesterone, and testosterone are among the most effective
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natural antiestrogens, and they are curative in many conditions that involve vascular leakage. Progesterone
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and pregnenolone have been called the antifibromatic steroids, and it has been used to treat many
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inflammatory and fibrotic diseases, including cancer.
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</p>
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<p>
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The antiserotonin drugs are being increasingly used to treat fibrotic diseases, and other problems related
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to vascular leakage.
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</p>
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<p>
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Antiinflammatory and anticoagulant things, especially aspirin and vitamin E, protect against the accelerated
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turnover of fibrinogen/fibrin caused by estrogen and the various inflammatory states.
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</p>
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<p>
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© Ray Peat 2006. All Rights Reserved. www.RayPeat.com
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</p>
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</body>
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