WE NEED SOME INFLAMMATION part 2

Not all inflammation is bad. As I briefly mentioned above we need to have a certain amount of inflammation. It is vital for proper functioning of the immune system, blood hemostasis mechanism and for tissue repair and healing. What we really need is an appropriate balance between inflammation and anti-inflammation. For example when a person steps on a nail and punctures the skin the inflammatory response serves to initiate healing of the wound and limiting the spread of infection and loss of blood. If you extinguished the body’s inflammatory response the person who cut himself would die of overwhelming infection or bleed to death. This is exactly what happens to a subset of people in Greenland who, due to their highly anti-inflammatory diet of marine blubber and fatty fish, tend to develop intracranial hemorrhage if they hit their heads hard. The high dose of fish oil prevents platelets from sticking together a little too well. They however have no heart disease and very little cancer!

As you can see from above in Figure 3 the hemostatic response (see part one from two weeks ago for diagram of the coagulation cascade) is to form a blood clot to stop hemorrhage. In step one, after exposure to collagen in a torn vessel or in our case a ruptured plaque “pimple,” you see the initial grouping together of platelets forming a platelet plug followed by the activation of plasma proteins which precipitate into a semisolid gel to solidify the plug.

In the cardiac patient, or anyone in a pro-inflammatory state where there is too much “inflammation,” platelet stickiness is much greater. Under these circumstances the system needs very little encouragement to form the initial platelet plug. It often happens with the rupture of an unstable plaque. All too frequently this leads directly to a heart attack, stroke, unstable angina or worse-sudden death. To help prevent this “hemostatic” mechanism from being too exuberant patients are put on anti-platelet drugs such as Plavix, aspirin, or my preference pharmaceutical grade fish oil. This tends to help prevent the initial cascade from occurring by blocking platelet stickiness and in the case of fish oil stabilizing the plaque cap as well. This hopefully will stop the major prerequisites leading to a heart attack.

Note however that the use of pharmaceutical anti-platelet drugs like Plavix does not directly address the root cause of the inflammation. It’s all still there toasting your endothelium and predisposing you to a coronary event. The Plavix or aspirin simply blocks the platelets ability to clump together which is only a manifestation of your inflammatory state. And yes, if you take too much Plavix and aspirin you may bleed too much usually in the form of excess bruising or nose bleeds. Sometimes Plavix can also cause excessive surgical bleeding in emergency neurosurgical cases (personal correspondence) or help to cause a brain hemorrhage if a patient hits his head too hard. Pharmaceuticals are not perfect. It’s far better to eliminate the cause of your inflammation. That’s what I did. I had one cardiac event years ago. I have never had another yet I do not take statins or Plavix or any other cardiac medication and never did. It’s all lifestyle changes which are the most powerful. In fact, only lifestyle changes can cure this condition not drugs.

Besides the hemostatic response we also have other processes that are occurring at the same time. There are two overlapping activities with the hemostatic response that occur in acute inflammation.

1. The vascular response
2. The cellular response

THE ACUTE INFLAMMATORY RESPONSE: BACTERIAL INFECTION, PUNCTURED SKIN & BLOOD VESSELS

Dear reader, please bear with me as I take you deeper into the strange world of acute inflammation. A knowledge of the acute and chronic immune response will help you to see how certain lifestyle choices have profoundly bad consequences. Let’s take the person stepping on a nail or thorn. In the vascular response the capillaries at the injury site dilate in reaction to this injury. At the same time the capillaries also become leaky to fluids and special cells floating in the blood. The capillary wall swells to allow the fluid component of blood, plasma, to leave the vessel. As fluid leaks out of the capillaries the blood becomes more viscous, blood flow slows down and clotting starts to occur just like in the hemostatic mechanism mentioned above in figure 3. These activities, along with the activation of pain signaling, lead directly to the cardinal signs: pain, swelling, redness and warmth mentioned above.

The cellular response phase is heralded by the migration of phagocytic cells, specialized cells which phagocytize or eat things. These are certain specialized leukocytes, which is just another name for white blood cells (or WBC’s). These WBC’s constrict through the lumen of the vessel into the tissues by a process called diapedesis. The leukocyte literally squeezes between endothelial cells which otherwise form an impregnable barrier. Like a ferret though a mouse hole the WBC’s migrate through the blood vessel and into the damaged tissues. With a bacterial invasion special leukocytes called neutrophils are the first to arrive. Upon leaving the blood vessel neutrophils enter the injured tissues and through the process of emigration move toward the damaged area following a chemical signal gradient (chemotaxis) like a bloodhound on a scent trail which guides them to the injury site. The neutrophil’s main role is consuming the bacteria through phagocytosis to help limit infection.

These neutrophils are eaten up by other special cells called monocytes which are located in blood vessels, (remember monocytes/macrophages because they from a pivotal role in the formation of plaque). Monocytes turn into macrophages (literally big eaters) before they consume anything. Monocytes then send numerous chemical signals to different cell lines to join the party. These chemical signals are called cytokines. Remember the term since many of these cytokines can be measured in the blood as a way of assessing the degree of inflammation in a patient.

The combination of dead WBC’s, bacteria, dead stuffed macrophages, cellular debris, plasma and other cellular components forms an inflammatory soup called an exudate. Depending on where the exudate comes from and the specific processes that make it, it can be a combination of fibrin, and many different dead cells including red and white blood cells. Exudates typically form the swelling and pus you see when an injury occurs. Pus then is just a collection of dead inflammatory cells filled with dead and eaten bacteria. The atheroma is similar in its makeup to this.

Over time the exudate is reabsorbed, the hemostatic plug reorganizes and tissue healing occurs. This is a simplified explanation of typical acute inflammatory response. I want to emphasize that this is normal and vital for good health. This is one of the basic ways for inflammation to display itself in the cardinal signs. This model is helpful to us when I explain how heart disease develops.

OTHER TYPES OF INFLAMMATION

Another type of inflammation occurs in the brain’s specialized immune cells called microglia. Although an atheroma (pimple) does not develop, there often exists a profound level of free radical formation and immune cell activation. This eventually kills the surrounding brain cells ultimately contributing to the three main neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD) and ALS. Autism may also get its jump wings from microglial activation. All four diseases are exponentially increasing in the developed world. It looks pretty certain that whatever we are doing to generate unprecedented levels of blood vessel inflammation it’s also contributing to brain inflammation.

Lastly, a generalized type of inflammation also manifests in roughly 80 million Americans which can lead to and promote these other two types of inflammation as well as promoting cancer. It’s called visceral fat (VF). VF is easily formed when there are chronically high levels of insulin in the patient. It’s composed of special fat cells which are powerful inflammatory factories called adipocytes. These cells generate dozens of pro-inflammatory immune cell signalers called cytokines and VF hormones called adipokines (from adipocyte). We call this specialized state of immune activation the metabolic syndrome which occurs when large amounts of VF accumulate ectopically just like cancer metastasis, to organs within the abdomen such as liver and pancreas leading to the classic beer belly or grain belly.

I mention these three even though there are literally hundreds of other types of inflammation depending on which organ is afflicted. But the Three Amigos of Inflammation are remarkably and uniquely endemic to our culture for reasons which will become apparent as we explore them in this book. I mention these in greater detail in Welcome to the Industrial Diner chapter.

A CLOSER LOOK

Now let’s delve deeper into the most prevalent and deadly, yet mysterious, disease to have ever arisen from the diesel fumed, concrete abattoir of first-world civilization. In this section we will discuss the theories on heart disease. There are two main theories and a popular press version. Parts of this section include excerpts from an emedicine article which may be difficult to read for a person without some prior knowledge in biochemistry, physiology, science or medicine. Having said that, I do not think it is overwhelming only that it would be helpful to have a science background. I provide this information so that the concerned reader can understand the true role of cholesterol, not the version that everyone thinks is factual. It is not crucial that you understand this theory only the points I make regarding lifestyle choices as a consequence of these facts.

Why is it more detailed? Here’s the deal, if you understand how heart disease really develops then you will also know how to keep it from manifesting in your body. There are many “causes” of heart disease besides cholesterol (which is NOT a cause). Yet few know and understand these dangerous “players” outside of research institutions. I reveal them here and in other appropriate areas of this book. Once you have this privileged knowledge you will be well equipped to prevent the biggest killer on the planet from seizing you. Make no mistake about it if you are a typical American or any other first-world inhabitant, then you are at high risk for atherosclerosis and all the other deadly problems that accompany it. Doctors-the Doc in the Box variety- currently feel pretty comfortable with what they think are the causes of atherosclerosis such as high cholesterol but most do not know about the true causes or cures.

This information clashes to some extent with mainstream Pharma-driven medicine. It diminishes cholesterol to its proper role and reveals other foods and habits that are far more dangerous than you probably thought. Therefore, I want you to know what the current consensus of opinion is on the etiology of the largest killer in the world. If you study this section you will know as much about the process of atherosclerosis as any doctor outside of a research scientist.

ATHEROSCLEROSIS

Atherosclerosis is the buildup of a waxy plaque on the inside of blood vessels. In Greek, athere means gruel, and skleros means hard. Atherosclerosis is often called arteriosclerosis. Arteriosclerosis (from the Greek arteria, meaning artery) is a general term for hardening of the arteries. Arteriosclerosis can occur in several forms, including atherosclerosis.^[1]

Atherosclerosis is the result of a long-standing, chronic, immuno-vascular response. Try to imagine if the person that stepped on the thorn from the previous example above kept the thorn in his foot. Let’s also say he would push it around every day, perhaps even pull it out, rub it into some dirt and then drive it back into his foot-ouch! What he is doing is adding new stimulus to the injury site before the acute inflammatory reaction has completed. This is how chronic inflammation starts. It’s the repeated injury and healing attempt over and over that drives the chronic process. The key is that the initial inflammatory stimulus does not go away-ever.

The inflammatory response in heart disease is similar to this repeated chronic injury scenario where the stimulus for injury persists. Instead of a thorn or rusty nail sticking in a foot our “stimulus” comes from the continuous exposure to other less obvious insults which we will discuss later. These insults can loosely be called risk factors. Some are very well known to you and others I’ll bet you never knew about. You may notice something interesting when we start talking about them. You’ll see that the entire first world is being crushed by the same risk factors while third world people suffer no such problems. This is our disease-like it or not. It’s a disease that has evolved from our general laziness and a life fixated on convenience.

Contrary to the acute response, chronic inflammation as it pertains to heart disease, involves several different actors. The response involves neutrophils even if there are no bacteria to stimulate their migration.[2] Monocytes (macrophage) and T-lymphocytes are the dramatis personae along with smooth muscle cells and fibroblasts which are involved in the chronic stages of inflammation leading directly to the atherosclerotic lesions we are discussing.

Figure 4 Components of an atheroma^[3]

In atherosclerosis thesmooth muscle cells and fibroblasts are induced to migrate from the tunica media where they are supposed to be into the subendothelial space called the tunica intima or just intima. This is ground zero for atheroma formation and this is where the lesions are found. One important observation is that normally the intima does not have smooth muscle cells or fibroblasts in it-but in chronic inflammation this is one of the hallmarks. The other parts of these lesions are made of oxidized omega 6 PUFA, and oxidized LDL cholesterol particles (oxLDL), macrophages and T-lymphocytes which are attracted to the area from the blood. They enter the vessel after the endothelium becomes damaged generally from cardiac risk factors we will discuss later.

I want to emphasize that plaque is not so much a simple cholesterol or lipid (fat) pool as it is an immuno-vascular collection of inflammatory cells: pus-like material more consistent with a whitehead. There are oxidized fatty acids present and oxidized lipoproteins (oxLDL), but no cholesterol per se. The only cholesterol found is that which is bound to its carrier lipoprotein and this carrier protein is always the small, readily oxidized form of LDL, the “bad” cholesterol.

The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can best be described, in aggregate, as an inflammatory disease.[4]

THE TOXIC ATHEROMA

Some of the chemical toxins associated with atheromas are products of lipid metabolism [such as oxidized omega 6PUFA], acids generated as part of cell necrosis, inflammatory cytokines, immune complexes, and other unknown factors. Oxidized LDL, one of the most well-known irritating agents (IAs), is believed to play a major role in the formation of the necrotic core. Reactive oxygen species are known to be highly toxic metabolites, causing immediate injury to cells, but the source of these free radicals has not been fully determined. Atheromas contain reactive oxygen species and may serve as a source of these toxic metabolites at the time of plaque rupture (PU).[5]

DIETARY EFFECTS ON ATHEROMA

….human atheroma is made up mostly of fibers of either collagen or fibrin, smooth-muscle cells or dead smooth-muscle cells, that it contains but little cholesterol, and that it is present in both men and women and in populations having little or no MI as well as in those where MI is the greatest cause of death….that MI is largely caused by coronary blood clots formed at the site of a break in the coronary artery endothelium; that the introduction of a new, unnatural dietary fatty acid–trans-trans linoleic acid–in margarine and refined vegetable oils in the 1920s, by inducing a deficiency of beneficial prostaglandin E1 (PGE1) while greatly increasing harmful thromboxane A2 (TXA2), caused vasoconstriction while the clumping of platelets was greatly increased, giving rise to the coronary blood clots that either cause or are part of the fatal process of MI….fostering the increase of dietary trans-trans linoleic acid in polyunsaturated vegetable fats at the expense of saturated animal fat, orthodox medicine is fostering a principle cause of MI as the cure.[6]

From the observations of the author in the above publication he notes that the atheroma is anything but full of cholesterol. That our dietary intakes of cheap seed oils and TFA are the “cause” of MI (heart attack). This observation relates to the eicosanoid cascade which I discuss in great detail in Welcome to the Industrial Diner. Here he mentions how one of the “good” eicosanoids, PGE1, is greatly decreased with the typical American diet rich in trans and omega 6 fats, at the expense of increased proinflammatory TXA2 which promotes platelet clumping. This TXA2 comes from an overabundance of omega 6PUFA and TFA in the diet. [6]

In the next installment we will  review the actual formation of the atherosclerotic plaque and the various theories of how it forms. One, the Drainpipe Theory, is the most popular and the least accurate, the Diet Heart hypothesis (saturated fat and cholesterol cause heart disease) was the predominant theory for years but it is finally crumbling thank god, the Response to Retention Hypothesis also fails to account for all the facts, and finally the most accepted theory is called the Response to Injury Hypothesis. Why is this important? Well Gus, it’s important to know the true mechanism so that we know how to treat or prevent it from occurring which is what this book is all about. Furthermore, by preventing this disease we concomitantly prevent most if not all of the diseases of modern society including many cancers!

Cheers!

[1] http://medical-dictionary.thefreedictionary.com/atherosclerosis. 12/24/2011

[2] Am. J. Epidemiol. (2001) 154 (8): 758-764. doi: 10.1093/aje/154.8.758 (http://aje.oxfordjournals.org/content/154/8/758.long) 04/21/2013

[3] (http://www.studyblue.com/notes/note/n/vessel-diseases/deck/2506590) 09/30/2013

[4] Ross R. Atherosclerosis – An inflammatory disease. N Engl J Med. 1999;340:115–126.

[5] (http://www.ncbi.nlm.nih.gov/books/NBK2024/) 06/07/2014

[6] Med Hypotheses. 1984 Nov;15(3):305-22.

Tags: chronic inflammation, inflammation, Three Amigos of Inflammation

Category: Inflammation, PREVENTIVE MEDICINE