# Fibrosis and Scleroderma

Category: Conditions

Also known as: fibrosis, scleroderma, tissue scarring, organ fibrosis

Fibrosis is an abnormal progression of normal tissue repair in which an energy-deficient, excitotoxic state drives the overproduction and rigidification of extracellular matrix, particularly collagen. Peat framed fibrosis not as a localized collagen disorder but as a general…

12 passages · 2 authors · 1996–2021 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/fibrosis-and-scleroderma

## Synthesis

**Fibrosis** is an abnormal progression of normal tissue repair in which an energy-deficient, excitotoxic state drives the overproduction and rigidification of extracellular matrix, particularly collagen. [Source 1, 9] Peat framed fibrosis not as a localized collagen disorder but as a *general defensive reaction* to excessive stimulation, oxygen deprivation, or chronic irritation, fundamentally linked to the processes of stress and aging. [Source 1, 6] This maladaptive response occurs when cells, starved of oxidative energy, shift from invisible restoration to crude provisional repair, progressively replacing functional tissue with inert, contracted scar. [Source 5] The phenomenon is universal, manifesting as **arteriosclerosis**, liver cirrhosis, pulmonary fibrosis, and the tough, rubbery texture of aged meat. [Source 1, 2]

The primary biochemical driver of fibrosis is the interaction between **estrogen** and **polyunsaturated fatty acids (PUFA)**. Estrogen activates phospholipase to liberate arachidonic acid, causing capillaries to leak fibrin into the extracellular matrix, where it serves as a scaffold for fibrotic deposition. [Source 2] Peat cited Alejandro Lipschutz's demonstration that chronic low-dose estrogen produces fibromas throughout the body, and noted that retroperitoneal fibrosis is now recognized as estrogen-driven and treatable with antiestrogenic drugs. [Source 2] Simultaneously, PUFA and their peroxidation products act as immunosuppressive inflammatory signals, increasing vascular permeability and inhibiting the proteolytic enzymes needed for collagen remodeling. [Source 2, 3] Ionizing radiation, heavy metals, and industrial particulates synergize with these factors by inflicting oxidative damage that converges on the same *reductive stress* and inflammatory cascade. [Source 2, 5]

**Scleroderma**, or systemic sclerosis, is the prototypical fibrotic disease and exemplifies this energetic-steroidal pathogenesis. It disproportionately affects women during reproductive years, often begins with edema and Raynaud's phenomenon, and involves excessive collagen and mucopolysaccharide deposition that mirrors hypothyroid myxedema. [Source 1, 10] Peat observed that **mere lack of oxygen** stimulates collagen formation, and that estrogen and adrenalin synergize to produce the vascular spasm seen in most patients. [Source 10] Hans Selye created an animal model by injecting iron to damage the liver—inducing estrogen excess—and then irritating the skin; vitamin E prevented the resulting sclerosis, implicating oxidative damage. [Source 4, 11] Dinkov has extended this framework by highlighting that NAD+ depletion directly causes fibrotic tissue formation identical to human scleroderma, and that restoring energy reserves via **nicotinamide** can fully prevent the structural lesions, corroborating Peat's view that the disease is an energetic deficiency in disguise. [Source 8]

The resolution of fibrosis depends on restoring oxidative energy production and opposing the excitotoxic, estrogenic milieu. Peat emphasized that **carbon dioxide**, produced by efficient mitochondrial respiration, inhibits inflammatory cytokines, reduces vascular leakiness, and creates the high CO₂/O₂ ratio characteristic of tissues that regenerate without scarring. [Source 3] Progesterone opposes estrogen at multiple points, inhibiting the phospholipase that releases arachidonic acid and blocking the pro-fibrotic effects on connective tissue. [Source 2, 10] Thyroid hormone (T3) accelerates the phagocytic removal of cellular debris essential for regenerative healing, while magnesium stabilizes ATP and prevents the intracellular calcium overload that drives calcification. [Source 3, 11] Additional protective factors include vitamin E to reduce free radical peroxidation, glycine-rich proteins to provide inhibitory amino acids, and avoidance of tryptophan and arginine excess to minimize serotonin and nitric oxide. [Source 7] Dinkov notes that **5-HT2B antagonists** like lisuride and ketotifen have been used successfully against fibrosis, further implicating serotonin in the fibrotic process. [Source 12]

## People also ask

### How does estrogen drive the formation of fibrotic tissue?

Peat argued that estrogen activates phospholipase to release arachidonic acid, causing capillaries to leak fibrin into the extracellular matrix where it acts as a scaffold for collagen deposition, and chronic low-dose estrogen can produce fibromas throughout the body.

### Why is restoring carbon dioxide production considered key to resolving fibrosis?

The corpus describes that carbon dioxide from efficient mitochondrial respiration inhibits inflammatory cytokines, reduces vascular leakiness, and creates a high CO₂/O₂ ratio that allows tissues to regenerate without scarring.

### What role does serotonin play in scleroderma according to this framework?

Dinkov noted that 5-HT2B antagonists like lisuride and ketotifen have been used successfully against fibrosis, implicating serotonin as a contributor to the fibrotic process.

## Related concepts

- [Arachidonic Acid](https://bioenergeticoracle.com/md/concepts/arachidonic-acid/index.md)
- [Essential fatty acids (EFA)](https://bioenergeticoracle.com/md/concepts/essential-fatty-acids-efa/index.md)
- [Insulin](https://bioenergeticoracle.com/md/concepts/insulin/index.md)
- [Lactic acidemia](https://bioenergeticoracle.com/md/concepts/lactic-acidemia/index.md)
- [Lipid Hypothesis](https://bioenergeticoracle.com/md/concepts/lipid-hypothesis/index.md)
- [Prostaglandins](https://bioenergeticoracle.com/md/concepts/prostaglandins/index.md)

## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — Fibrosis: Estrogen, stiffness, excitotoxicity, aging — a problem more general than collagen disease

Ray Peat · Article · 2001

> For example, when a cell is deficient in vitamin E it loses molecules such as ATP and proteins, that diffuse out into the extracellular spaces. When cells are in an energy deficient state, as in hypothyroidism, they are in this leaky, edematous state.
>
> This state of near exhaustion is similar to the "excitotoxic" state that's caused by an imbalance between stimulation and energy production. In the brain, excitotoxins have been found to produce a kind of fibrosis, in which the cells that normally produce the myelin sheath surrounding nerve axons begin producing collagen, and appear to change into a type of cell (Schwann cell) that is not normally found in the brain. The production of collagen seems to be a very basic kind of defensive reaction to excessive stimulation or oxygen deprivation. This makes it possible to see "excitotoxicity" as a general process, that includes the kind of fibrosis and calcification of skin that Hans Selye produced (by combining vitamin E deficiency with heavy metal toxicity and local irritation), as well as the aging of brain cells produced by prolonged estrogenic stimulation.
>
> Scleroderma, like the other "collagen diseases," affects women (during their reproductive years) much more often than men. Retroperitoneal fibrosis, which can seriously damage the kidneys and other abdominal organs, has been compared to uterine fibroid tumors, and it is commonly treated successfully with the antiestrogenic drug, tamoxifen. Tamoxifen has also been used to treat keloids and to prevent abnormal scars in plastic surgery. (I have seen keloids regress quickly following the application of vitamin E with antiestrogenic hormones.) The fibrotic response to the excitotoxic imbalance can be seen in practically all chronic and degenerative diseases.
>
> Fibrosis is an abnormal progression of the normal formation of fibrous material between cells, and it usually involves an increase in the volume of the extracellular material, and an increase in the percentage of collagen in that matrix, and an increased rigidity of the collagen that results from chemical cross-links, that are analogous to the polymerization of a plastic, or the vulcanizing of rubber. Arteriosclerosis is probably the best known medical example of tissue fibrosis, but it's the same phenomenon that makes the meat from an old animal tough and rubbery.

### Source 2 — Fats and degeneration

Ray Peat · Article · 2013 · https://raypeat.com/articles/articles/fats-degeneration3.shtml

> But, in the face of the immense amount of propagandistic "health" claims that have been made against the saturated fats, it's instructive to look at some of their actual effects, especially on the clotting system, and the related fibrotic reactions.
>
> The saturated fatty acids are very unreactive chemically. Coconut oil, despite containing about 1% of the unstable PUFA, can be left in a bucket at room temperature for a year or more without showing any evidence of deterioration, suggesting that the predominance of saturated fat acts as an antioxidant for the unsaturated molecules.
>
> In the body, the saturated fats seem to act the same way, preventing or even reversing many of the conditions caused by oxidation of fats.
>
> The stress-induced liberation of arachidonic acid causes blood vessels to leak, and this allows fibrin to escape from the blood stream, into the basement membrane and beyond into the extracellular matrix, where it produces fibrosis. (Cancer, autoimmune diseases, and heart disease involve the same inflammatory, thrombotic, fibrotic processes as the nominal fibroses.) Scleroderma, liver cirrhosis, fibrosis of the lungs, heart, and other organs, and all the diseases in which fibrous tissue becomes dense and progressively contracts, involve similar processes, and the treatments which are successful are those that stop the inflammation produced by the oxidation of the polyunsaturated fatty acids.
>
> Retroperitoneal fibrosis is now known to be produced by estrogen, and is treated by antiestrogenic and antiserotonergic drugs, but as early as 1940 Alejandro Lipschutz demonstrated that chronic exposure to very low doses of estrogen produced fibromas in essentially every part of the body.
>
> Earlier, Loeb had studied the action of large doses of estrogen, which produced fibrosis of the uterus, as if it had accelerated aging.
>
> Following Lipschutz' work, in which he demonstrated the "antifibromatogenic" actions of pregnenolone and progesterone, several Argentine researchers showed that progesterone prevented and cured abdominal adhesions and other fibrotic conditions, including retroperitoneal fibrosis.
>
> Since estrogen produces both leakiness of the capillaries and excessive formation of fibrin, its effects will be seen first in the organs where it concentrates, but eventually anywhere capillaries leak fibrin.

### Source 3 — Regeneration and degeneration - Types of inflammation change with aging

Ray Peat · Article · 2012 · https://raypeat.com/articles/articles/regeneration-degeneration.shtml

> For example, the membranes lining the mouth, and the bones and bone marrow, and the thymus gland are able to regenerate without scarring. What they have in common with each other is a relatively high ratio of carbon dioxide to oxygen. Salamanders, which are able to regenerate legs, jaw, spinal cord, retina and parts of the brain (Winklemann & Winklemann, 1970), spend most of their time under cover in burrows, which besides preventing drying of their moist skin, keeps the ratio of carbon dioxide to oxygen fairly high.
>
> The regeneration of finger tips, including a well-formed nail if some of the base remained, will occur if the wounded end of the finger is kept enclosed, for example by putting a metal or plastic tube over the finger. The humidity keeps the wound from forming a dry scab, and the cells near the surface will consume oxygen and produce carbon dioxide, keeping the ratio of carbon dioxide to oxygen much higher than in normal uninjured tissue. Carbon dioxide is being used increasingly to prevent inflammation and edema. For example, it can be used to prevent adhesions during abdominal surgery, and to protect the lungs during mechanical ventilation. It inhibits the formation of inflammatory cytokines and prostaglandins (Peltekova, et al., 2010; Peng, et al., 2009; Persson & van den Linden, 2009), and reduces the leakiness of the intestine (Morisaki, et al., 2009). Some experiments show that as it decreases the production of some inflammatory materials by macrophages (TNF: Lang, et al., 2005), including lactate, it causes macrophages to activate phagocytic neutrophils, and to increase their number and activity (Billert, et al., 2003; Baev & Kuprava, 1997).
>
> Factors that are associated with a decreased level of carbon dioxide, such as excess estrogen and lactate, promote fibrosis. Adaptation to living at high altitude, which is protective against degenerative disease, involves reduced lactate formation, and increased carbon dioxide. It has been suggested that keloid formation (over-growth of scar tissue) is less frequent at high altitudes (Ranganathan, 1961), though this hasn’t been carefully studied. Putting an injured arm or leg into a bag of pure carbon dioxide reduces pain and accelerates healing.

### Source 4 — Diagnosing Porphyria for Labor and Industries Claims

Ray Peat · Newsletter · Apr 1996

> I have known women who developed scleroderma after beginning the use of estrogen, and who are reluctant to stop, because they had been told that estrogen would protect them from osteoporosis and heart disease. Men who have had a diagnosis of scleroderma have told me that with the use of thyroid and magnesium supplements, Epsom salts baths, and topical progesterone and vitamin E, their symptoms regressed.
>
> Polymyositis sometimes leads to calcification, and this would be expected if the problem is related to mitochondrial respiration, as is now generally thought to be the case; thyroid and magnesium are often the factors needed to normalize mitochondria and prevent calcification.
>
> Tumoral calcinosis is sometimes treated as a variant of scleroderma, but it is very different, and tends to be localized, without internal complications. I think many people get minor bony excrescences (bone spurs, osteophytes, exostoses, hyperostoses) during puberty, or at other times of hormone imbalance, which often disappear spontaneously, but this probably represents the same basic process, and would have very little to do with the severe oxygen deficiency states in which collagen synthesis is overstimulated. Growth hormone and prolactin imbalances have been suspected to have a role in some of these growths. (Both of these pituitary hormones are elevated by estrogen, and hypothyroidism is often the cause.) Progesterone, thyroid, bromocriptine, and other things are available to normalize the pituitary, when that is responsible.
>
> A weakened ability to oxidatively produce energy can lead to the maladaptive over-production of collagen, porphyrins, and red blood cells. Considered together, I think the mechanisms involved in these diseases argue for the importance of the nutritional-environmental approach to health care. The medical/bureaucratic preference for a genetic rationale for disease has overtones of eugenics. When the state gets involved in genetics, eugenics, or medicine, they had better keep their own scientific standards at least as high as those they demand of the people they disagree with.

### Source 5 — Particles in Context

Ray Peat · Newsletter · 2019

> When the organism’s situation isn’t good, instead of invisible restoration there is inflammation, a process in which crude provisional repairs are made, so that the damaged tissue doesn’t continue to demand resources that aren’t available. A scar is formed, a relatively inert fibrotic tissue replaces the fully functional tissue. This happens progressively with continued exposure to harmful factors, degrading the lungs, heart, blood vessels, gonads, liver, kidneys, brain . . . .
>
> Very different factors can have additive or synergistic effects leading to the same conditions of inflammation and fibrosis. Ionizing radiation, particulate matter, and estrogen excess interfere with the system in different ways, but all produce reductive stress, inflammation, collagen synthesis, and loss of differentiated cellular functions.
>
> The characteristic diseases of our time—cardiomyopathy, pulmonary hypertension, neurological disorders, Parkinson’s disease, Alzheimer’s disease, insulin resistance and metabolic syndrome, rheumatoid arthritis, kidney diseases, and cancer (Pérez-Torres, et al., 2017)—as well as trauma, shock, sepsis, and infection, involve reductive stress, the inability to maintain cell respiratory energy production, and its associated destructive inflammatory processes.
>
> [references]

### Source 6 — Diabetes, scleroderma, oils and hormones

Ray Peat · Article · 2006 · https://raypeat.com/articles/articles/diabetes.shtml

> # Diabetes, scleroderma, oils and hormones
>
> The basic argument: Stress and aging make cells less responsive in many ways by damaging their ability to produce energy and to adapt. The polyunsaturated fats are universally toxic to the energy producing system, and act as a "misleading signal" channeling cellular adaptation down certain self-defeating pathways. Diabetes is just one of the "terminal" diseases that can be caused by the polyunsaturated vegetable oils. Coconut oil, in diabetes as in other degenerative diseases, is highly protective. When the oral contraceptive pill was new (Enovid), it was found to produce signs of diabetes, including decreased glucose tolerance. Spellacy and Carlson (1966) suggested that an elevation of circulating free fatty acids might be responsible, and remarked that "Free fatty acids can block the Krebs cycle, with relative insulin action resistance resulting." "The potential danger of the oral contraceptives is one of prolonged pancreatic stimulation." Recent papers are reporting that the estrogen used to "treat menopause" causes an increase in free fatty acids. Spellacy and Carlson suggested that estrogen's effect was mediated by growth hormone, and that is now the consensus. Women are much more likely than men to develop diabetes. Ephraim Racker observed that free unsaturated fatty acids inhibit mitochondrial respiration, and recent studies are finding that free linoleic and linolenic acids act as intracellular regulators, stimulating the protein kinase C (PKC) system, which is also stimulated by estrogen and the (cancer promoting) phorbol esters. They stimulate the cell while blocking the energy it needs to respond.
>
> Scleroderma, or systemic sclerosis, is a supposedly mysterious condition in which tissues harden, with an excessive deposition of fibrous material. Besides hardening the skin, it can involve fibrosis of the heart and other organs, and can cause changes in blood vessels of the kidneys like those seen in some types of hypertension, and often involves Raynaud's phenomenon and osteoporosis of the fingers. (Silicone functions as an adjuvant, making exposure to irritants, solvents or infections more harmful. This seems to be the reason for the association between breast implants and scleroderma.)

### Source 7 — Fibrosis: Estrogen, stiffness, excitotoxicity, aging — a problem more general than collagen disease

Ray Peat · Article · 2001

> The calorie-restricted diets that slow the aging process reduce the accumulation of the unstable fats and the heavy metals. Vitamin E reduces the vascular leakiness and the free radical peroxidation that are so closely involved in fibrosis. Since serotonin and nitric oxide are involved in these processes, they should be minimized by keeping carbon dioxide production high (by optimizing thyroid function), and by eating proteins that have a safe balance of the amino acids. Too much arginine increases nitric oxide formation, and too much tryptophan increases serotonin production. Too much glutamic acid, aspartic acid, and cysteine can be directly excitotoxic, and the metabolites of cysteine include proinflammatory homocysteine, which can disrupt collagen structure.
>
> Since estrogen is often a promoter of fibrosis, acting in a variety of ways, it should be kept under control by eating enough protein, keeping thyroid function relatively high, and if necessary by using progesterone and other antiestrogenic hormones. A protein deficiency is thrombogenic (clot forming), and probably excitotoxic.
>
> Magnesium, taurine, and niacinamide have many protective functions, and can help to reduce or reverse inflammatory and fibrogenic processes.
>
> [references]

### Source 8 — Niacinamide as treatment for scleroderma (systemic sclerosis)

Georgi Dinkov · Article · Feb 8, 2021 · https://haidut.me/?p=1385

> Yet another “incurable” disease has been demonstrated to be nothing more but energetic deficiency in disguise. According to mainstream medicine, scleroderma (also known as systemic sclerosis) is an incurable chronic, autoimmune, progressive, fibrotic disease that attacks virtually all organs and can lead to significant disability and even death if it affects some of the more vital organs such as lungs, heart, pancreas, etc. No known treatment for the condition exists, and as such treatment is “supportive” – i.e. mainly glucocorticoids for acute exacerbations, and immunosuppressive drugs for chronic “treatment”. In other words, not much different than other autoimmune conditions such as multiple sclerosis, Lupus, rheumatoid arthritis, psoriasis, etc. Interestingly enough, it has been known for at least 5 decades that the disease has an endotoxin component as a cause since administering TLR4 (endotoxin receptor) antagonists such as ketotifen or Benadryl (diphenhydramine) has been able to cure the disease in some patients and greatly retard its progression in others. The fact that endotoxin has a causative role in this condition should have directed the medical authorities to dig further into the energetic aspect of this disease, but not much has been done in this direction considering that medicine does not believe functional disorders (energetic deficiency) can lead to structural ones (systemic sclerosis). Now, the study below adds more evidence in favor of the crucial role metabolism/energy plays in this disease. It demonstrates that depletion of NAD+ can directly lead to the formation of fibrotic tissue identical to the one seen in humans with the condition. Conversely, alleviating the NAD+ depletion by blocking its consumption (CD38 inhibitor) or providing an NAD+ precursor such as nicotinamide (riboside) can fully prevent the structural lesions associated with the disease. The HED of nicotinamde (riboside) was 30mg/kg and the treatment was administered for just 3 weeks. Just as importantly, the study found that the formation of scars is entirely controlled by energy availability. In other words, the higher the metabolic rate and the higher the energetic production/reserves of the organism, the less scar formation occurs (from any cause).

### Source 9 — Fibrosis: Estrogen, stiffness, excitotoxicity, aging — a problem more general than collagen disease

Ray Peat · Article · 2001

> Arteriosclerosis is probably the best known medical example of tissue fibrosis, but it's the same phenomenon that makes the meat from an old animal tough and rubbery.
>
> Although "stiffness" is a familiar term in engineering and biology, it has some different meanings in different situations. When a tissue swells up with water until it's tight, it is stiffer than in its natural condition. The material of tendons and ligaments gets stiffer by increasing its density and toughness. When a bone gets old, it gets brittle and weak, and in one sense it is stiffer than a child's bone, since a child's bone can be deformed without breaking: While the engineering definitions can't be applied to all tissues in a simple way, biologically it's useful to think of stiffness as something that progresses along with fibrosis, as the function of a tissue decreases. In the first stage of tissue injury, swelling stiffens a tissue; after prolonged edema, there may be an increased volume and concentration of collagen around cells; finally, the density of the collagen can increase, and can calcify, as in the sclera of the eye, the arteries, heart valves, pericardium, and even the heart muscle itself.
>
> In diseases of stress and aging, there is a general inflammatory state, that can end in multiple organ failure. Congestive heart failure illustrates some of the effects of this energy-poor, inflamed and edematous state: The heart's function is reduced because of stiffness caused by increased water and calcium in the cells; at the same time, arteries are stiff and resistant, impairing the flow of blood and making regulation of blood pressure difficult. In chronic hypothyroidism, the heart gradually becomes fibrotic, and this provides an opportunity for calcification to occur.
>
> If a callus is a metaphor for the normal, protective function of connective tissue, then a corn is a metaphor for the harmful overdevelopment of the protective reaction. The ordinary minor mechanical tensions and pressures that occur in any living animal, as well as the biochemical gradients produced by metabolizing cells, shape the connective tissues that keep cells in their particular place in the organism. When gelatin, made by boiling connective tissues in water, is injected into a growing organism, the randomly arranged molecules of the melted collagen can be seen to organize themselves back into the coherently aligned cable-like structures of normal connective tissue.

### Source 10 — Diagnosing Porphyria for Labor and Industries Claims

Ray Peat · Newsletter · Apr 1996

> It was probably this medical association that caused Hans Selye to create the animal model, in which the injection of iron contributed to the development of scleroderma. Injected iron damages the liver, and practically any kind of liver damage leads to estrogen excess and a chronic stress-like adaptive response.
>
> Scleroderma used to be described as one of the collagen diseases, because similar changes in blood vessels and connective tissues were seen in systemic lupus erythematosus, rheumatoid arthritis, polyarteritis, drug hypersensitivity, etc.
>
> Scleroderma (similar to several other autoimmune diseases) is much more common in women than in men, and animal models for several autoimmune diseases can be produced with estrogen treatment. Scleroderma often begins with edema of the extremities, Raynaud's phenomenon, and muscle weakness or polymyositis, which are commonly seen in hypothyroidism/hyperestrogenism.
>
> It is generally agreed that collagen is overproduced in scleroderma, and there is evidence of increased mucopolysaccharides in the skin. This is reminiscent of hypothyroid myxedema; it has been suggested that mucopolysaccharides can act as a matrix for calcification. Estrogen stimulates the formation of collagen, and increases its age-like properties, and progesterone opposes some of these pro-aging effects on connective tissues. Mere lack of oxygen stimulates collagen formation, and the opposing effects of estrogen and progesterone on tissue oxygenation can account for many of the tissue changes they produce.
>
> Oxygen deprivation causes tissues to retain calcium (and iron), as does estrogen in many cases, being similar to aging in promoting cellular uptake of calcium. Since the porphyrins strongly bind metals, it has been suggested that they may have a role in mediating the deposition of metals in stressed tissues. Paroxysmal vasospasm occurs in about 90 of scleroderma patients, and estrogen and adrenalin are known to synergize in producing vascular spasm; hypothyroidism normally involves elevations of both estrogen and adrenalin.
>
> I have known women who developed scleroderma after beginning the use of estrogen, and who are reluctant to stop, because they had been told that estrogen would protect them from osteoporosis and heart disease.

### Source 11 — Diabetes, scleroderma, oils and hormones

Ray Peat · Article · 2006 · https://raypeat.com/articles/articles/diabetes.shtml

> This could explain the presence of chemically active iron, but an actual increase in the iron concentration suggests that there has been prolonged injury (oxidative stress) to the cell, with increased production of the heme group, which binds iron.
>
> Hans Selye found that he could produce scleroderma (hardening and calcification of the skin) in rats by giving them a toxic dose of a heavy metal, and then irritating the skin a little by plucking hair.
>
> Iron is now tending to be recognized as a factor in inflammation.
>
> Vitamin E was able to prevent the development of scleroderma under Selye's experimental conditions, suggesting that the irritation allowed the heavy metal to cause oxidative damage to the skin.
>
> Selye found other ways to cause calcification of tissues, including the walls of arteries, but he directed most of his attention to the role of "pro-inflammatory" hormones. A decreased blood supply was often used to predispose an organ to calcification.
>
> In diabetes, a characteristic feature is that the blood supply is relatively remote from cells in muscle and skin, so the oxygen and nutrients have to diffuse farther than in normal individuals, and the ATP level of cells is characteristically lower than normal.
>
> In blood cells, both red (Garnier, et al.) and white cells are probably more rigid in diabetes, because of lower ATP production, and higher intracellular calcium and sodium.
>
> Magnesium in the cell is largely associated with ATP, as the complex Mg-ATP. When ATP is "used" or converted to ADP, this lower-energy substance associates with calcium, as Ca-ADP.
>
> In a hypothyroid state, the energy charge can be depleted by stress, causing cells to lose magnesium. ATP is less stable when it isn't complexed with magnesium, so the stress-induced loss of magnesium makes the cell more susceptible to stress, by acting as a chronic background stimulation, forcing the cell to replace the ATP which is lost because of its instability. In this state, the cell takes up an excess of calcium.
>
> The picture that I think explains many of the features of diabetes is that an energy deficit produces an alarm state, causing increased production of adrenalin and cortisol.

### Source 12 — IdeaLabs Forum Q&A — Lisuride

Georgi Dinkov · Forum Q&A · Aug 5, 2016

> **Owen B:** (2018-08-23) I have a pretty well developed skin inflammation with fibrosis. Not scleroderma/ edema. The dermatologist is really of no help. All he wants to do is treat it as an infection. It's not an infection. Lisuride of any help for something like this?
>
> **Georgi Dinkov:** (2018-08-28) I can't discuss specific conditions but 5-HT2B antagonists like lisuride and ketotifen have been successfully used for such issues. Google "ketotifen fibrosis" for more info.
>
> **thomas00:** (2018-10-25) Will Lisuride be damaged if exposed to a bit of heat (~4oC) in the mail? thanks
>
> **Georgi Dinkov:** (2018-10-25) It depends on how long. Up to a day, probably not much, but several days could be an issue.
>
> **ddjd:** (2018-10-26) what could possibly be the reason for the constipation i experience from lisuride?
>
> **Georgi Dinkov:** (2018-10-26) Serotoni antagonism and/or dopamine agonism. It is a common side effects of both effects. Wikipedia mentions it too.
>
> **ddjd:** (2018-10-26) I was thinking that gut motility mainly relates to 5-ht3 and I know lisuride doesnt act on that particular receptor

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