Thursday, March 11, 2010

Tumour necrosis factor to the rescue. No, really.

Abstract We examined the effects of lacking tumor necrosis factor α (TNFα) on the healing process of a cutaneous wound in mice using TNFα-deficient mice. A full-thickness circular cutaneous wound 5.0 mm in diameter was produced in the dorsal skin of wild-type (WT) or TNFα-null (KO) mice. After specific intervals of healing, the healing pattern was evaluated by macroscopic observation, histology, immunohistochemistry, or real-time reverse transcription-polymerase chain reaction. Effect of Smad7 gene transfer on the healing phenotype of KO mice was also examined. The results showed that loss of TNFα promotes granulation tissue formation and retards reepithelialization in a circular wound in mouse dorsal skin. Immunohistochemistry showed that distribution of macrophages and myofibroblasts in newly generated granulation tissue seemed similar between WT and KO mice. However, lacking TNFα enhanced mRNA expression of TGFβ1 and collagen Iα2 in such tissue. Smad7 gene transfer counteracted excess granulation tissue formation in KO mice. In conclusion, lacking TNFα potentiates Smad-mediated fibrogenic reaction in healing dermis and retards
reepithelialization in a healing mouse cutaneous wound."

From wikipedia;

Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals.

Tumour necrosis factor alpha "inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase."

Whatever that means. But anyways, it reduces the action of insulin in the cell. Which is, insulin resistance. Bad, right? But if it doesn't do that, what happens to wound healing?

If you block glucose metabolism in nematode worms, they live twice as long. And collagen one production is decreased. Glucose metabolism is clearly important to collagen formation. And healing. Probably in arteries as well as skin.

And the disregulation of energy source, the wrong blend of glucose and fat metabolism, should lead to what? Poorly-healed wounds. Including in arteries. Too little collagen (not enough glucose) will make for patches lacking strength. Too much collagen will make for well, in the extreme, wounds that don't even close properly?

Okay. So tumour necrosis factor alpha induces insulin resistance in an arterial lesion. Which should down-regulate insulin signalling. Which should stimulate the oxidation of fat, which will facilitate the healing process. So LDL to the rescue! LDL cholesterol shows up with lots of tasty fat, mitochondria start to party! So some serious healing should take place. What goes wrong?

Why do you end up with an atherosclerotic plaque, poorly healed, with a core of lipid-rich pudding?

Well, why do muscle cells fill up with fat in lipid storage myopies? One form of lipid storage myopy occurs when muscle cell leptin receptors are deficient in activity or presence. Leptin facilitates the use of fat for energy. Fat cells are less sensitive to their own leptin than other cells; but they do have leptin receptors.

Atherosclerotic plaque, the human kind with the lipid core, looks an awful lot like a wound with a lipid storage disease. To the untrained eye, anyways, and that's the only kind I've got. Lipid storage disease is really just a relative inability to metabolize lipids for energy. Something keeps the whatever-you-call-em, the immune and repair cells from properly metabolizing fat.

What does this? How about signing up for a study of the effect of massive doses of certain antioxidants on the development of heart disease? Messing around with your antioxidant status can seriously mess up your ability to metabolize fat. The mainstream calls this anti-inflammatory; less free radicals, less oxidized cholesterol, less heart disease. Well, that just plain didn't work out.

One thing about omega 6 fatty acids; they contain a whole crapload of vitamin e. The vitamin e is there to protect the fatty acids from oxidation; including the type encouraged by mitochondria.

Of course, this predicts that interventions that facilitate the use of fat for energy will help arteries heal, at least when the thing going wrong is arterial lipid storage disease.

"ApoE Promotes the Proteolytic Degradation of Amyloid Plaque"

That isn't quite the name of that study, there was a greek letter in there that pasted wrong. There's a product called Amylin; Dr Bernstein uses it for some of his patients to reduce cravings for sugar, and there are some studies showing it increasing leptin sensitivity. Amylin is a drug based on the hormone amyloid. Amyloid is produced in the pancreas, along with insulin. It's also produced in the brain.

APOE-4: The Clue to Why Low Fat Diet and Statins may Cause
by Stephanie Seneff

Amyloid-beta (also known as "abeta") is the substance that forms the famous plaque that accumulates in the brains of Alzheimer's patients. It has been believed by many (but not all) in the research community that amyloid-beta is the principal cause of Alzheimer's, and as a consequence, researchers are actively seeking drugs that might destroy it. However, amyloid beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate (the product of anaerobic glucose metabolism) into lactate, through an anaerobic fermentation process, with the further production of a substantial amount of ATP.

People with APOE4 genotype get more heart disease, more alzheimer's. Amyloid-beta accumulates in the brains of Alzheimer's patients. Amyloid-beta promotes the proper metabolism of carbohydrates, that's a good thing. But there's a time when you don't want to promote the metabolism of glucose, lactate, etc.-- that is, when high-gear mitochondrial respiration, the preference of fat for energy, and the spewing out of free radicals is desirable. Like um, when you're trying to clear up a serious case of arterial lipid storage disease, for instance.

Let's look at some mice.

Abstract—Most previous studies of atherosclerosis in hyperlipidemic mouse models have focused their investigations on lesions within the aorta or aortic sinus in young animals. None of these studies has demonstrated clinically significant advanced lesions. We previously mapped the distribution of lesions throughout the arterial tree of apolipoprotein E knockout (apoE-/-) mice between the ages of 24 and 60 weeks. We found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, exhibits a highly consistent rate of lesion progression and develops a narrowed vessel characterized by atrophic media and perivascular inflammation. The present study reports the characteristics of advanced lesions in the innominate artery of apoE-/- mice aged 42 to 60 weeks. In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap. By 60 weeks of age, the lesions are characterized by the presence of collagen-rich fibrofatty nodules often flanked by lateral xanthomas. The processes underlying these changes in the innominate artery of older apoE-/- mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque.

So what have we here? Knock out apoE. If I'm looking at this right, this improves glucose metabolism, the feeding of lactic acid into the Krebs cycle. No need for fat here, we're really good at burning glucose! Life is good!

Except that it isn't. "Collagen-rich fibrofatty nodules"-- um, encouraging glucose metabolism seems to have caused excess collagen growth.


In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap

This is really freaking bad. Really really really bad. Loss of the fibrous cap? What could have caused that? And does this remind anybody of the study at the top of this page, the one that says

The results showed that loss of TNFa promotes granulation tissue formation
and retards reepitheialization in a circular wound in mouse dorsal skin

Doesn't the effect of an ApoE type that just happens to be associated with increased levels of a hormone that facilitates glucose metabolism on healing in mouse arteries sort of kind of resemble the effect of the lack of a hormone that discourages glucose metabolism on healing in mouse skin? Oh my, what a startling coincidence!

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