The Inflammation Processby Patrick Quanten MD
Dealing with injury and infection is vital to survival. It is hardly surprising then, that all animals possess mechanisms designed specifically to deal with wound healing and microbial defence. In mammals such as ourselves, these mechanisms are remarkably complex and, when they function correctly, produce an exquisitely choreographed suite of reactions which biologists are only now beginning to fully appreciate. The first stage in this process is known as the acute phase response, or, less technically, as inflammation.
Traditionally Western medicine has recognised the four signs of inflammation as tumor, rubor, calor and dolor - swelling, redness, heat and pain. Besides these physical changes, there are also important psychological ones, including lethargy, apathy, loss of appetite and increasing sensitivity to pain - a suite of symptoms that are collectively known as "sickness behaviour". Taken together, the four classic signs of inflammation and the psychological symptoms of sickness behaviour constitute the complex set of processes referred to as the acute phase of response.
The value of feeling bad is nowhere better illustrated than in the case of pain. Pain, as everyone knows, is a great protector. The acute pain, as caused by you touching a hot stove, is obviously beneficial, making you move away quickly from damaging objects. Even more important, however, is the second phase of pain that tends to follow the acute pain. Acute pain is sharp and stabbing, and ends when you are no longer in contact with the source of damage; the second type of pain is deep and spreading, and can last for minutes, hours, days or even months. This kind of pain is not caused by pressure or heat from the outside world, but by chemicals released by the body itself. And, unlike acute pain, which produces a rapid movement, the second type of pain causes you to keep the wounded area as still as possible, and encourages you to take extra care to shield the area from fresh injury while the process of repair is completed.
The same applies to all other aspects of the acute phase response. Swelling, for example, is also a defensive process, caused by the leakage of plasma and the migration of immune cells into the area of damaged tissue. All bodily damage, whether caused by injury or infection, consists of broken cells, and when the walls of a cell rupture, an array of molecules which would not otherwise be released, spill out into the surrounding tissue. Some of these molecules trigger the sensory nerves to produce the ongoing, second type of pain just described. The sensory nerves also react by causing the blood vessels to widen, increasing local blood flow (Redness), and making the walls of the blood vessels more permeable. With greater blood flow, more white blood cells, the infantry of the immune system, can be carried to the site of the injury. The greater permeability of the blood vessel walls enables the white blood cells to flow out of the arteries and veins into the surrounding tissue to defend against possible bacterial invaders. If no bacteria have found their way into the wound, particular white blood cells known as macrophages clear up the debris of the chattered cells by engulfing and digesting it. If bacteria have gained a foothold and started to multiply, the white cells form a barrier to create a pus-filled abscess in which the blood fluid, the serum, plays a key role in healing.
Besides clearing up the debris and attacking bacteria themselves, the macrophages also release a number of chemical messengers. These signalling molecules, or cytokines, play a vital role in co-ordinating the acute phase response by facilitating both short-distance communication among the immune cells themselves and long-distance communication between the immune cells at the injured site and the brain.
Increasing levels of prostaglandin E2 in the brain induce an area called the hypothalamus to turn up the body's thermostat a notch. Suddenly, the same external temperature feels colder, and various means are employed to restore the subjective impression of warmth. These include involuntary processes such as shivering, which generates heat by movement, and voluntary behaviour such as putting on more clothes, finding a warm radiator to sit next to, and so on.
Like pain and swelling, fever plays a vital part in defending the body against infection. Many bacteria reproduce most effectively at normal body temperature. So by raising body temperature the rate at which the bacteria can divide is slowed down. Fever has the opposite effect on most immune cells, causing them to divide more quickly. So fever both slows down the spread of the infection and accelerates the counterattack by the immune system.
All injuries and infections, as stated above, cause a fever. This might only manifest itself in a localised heat, and does not always produce an overall increase of the body temperature.
Lethargy, Apathy and Loss of Appetite
Fever is not cheap. The body has to work hard to raise its temperature. In mammals, an increase of just one degree Celsius in core body temperature requires around 10-13 per cent more energy than normal. To balance the energy budget, savings must be made elsewhere, and the brain accordingly generates feelings of lethargy and apathy which reduce the energy expended in behaviour. Sick people generally do not feel like doing very much, but this is not because they have simply "run out of energy". They are merely saving their energy to use in other ways.
Mechanism of the Acute Phase Response
In response to acute damage or entrance of foreign material monocytes enlarge and synthesise increased amounts of enzymes which help to break down the material. In doing so they are transformed to more active phagocytes called macrophages. Monocytes are formed in the bone marrow, enter the blood stream and have a longer life than neutrophils (T and B lymphocytes, "white blood cells"), estimated at 12 to 24 hours. Monocytes respond to chemotactic and immobilising factors (migration inhibitory factor) excreted by lymphocytes. This allows them to "stick" at the debris site.
Macrophages have surface receptors for antibodies and are capable of synthesising various proteins as messengers. An important function of the macrophage is the presentation of debris material to B and T cells. Large molecules or particular substances, however, require digestion by the macrophage before they can be recognised by the other cells of the immune system. Bits of these materials will be displayed on the surface of the macrophage and via contact stimulate both B and T cells into appropriate action.
Lymphocytes (including B and T cells) mainly produce immunoglobulins (antibodies) and are also responsible for cellular immunity. Cellular immunity is involved in delayed hypersensitivity (allergies and various overreactions of the body) and homograft rejection. Lymphocytes can also damage foreign cells (bacteria, parasites, fungi, etc.). Human lymphocytes are formed chiefly in the bone marrow. Normal T cells develop only in the presence of a normal functioning thymus. Long lived lymphocytes are primarily T cells, that recirculate through the spleen and the lymph nodes, thoracic duct and bone marrow, leaving and re-entering the circulation repeatedly. There are subpopulations of T cells which serve to enhance (helper T) or reduce (suppressor T) B-cell responses. It is not yet known precisely how the various surface receptors on T and B cells influence cell function, but they are probably involved in antigen recognition and cell-to-cell interactions with macrophages and other lymphocytes.
We see the various cells involved in the process under our powerful microscopes in still pictures. We also can measure various substances at various points throughout the inflammation process and we can identify certain specific sites on the cell surface. From this information we piece together the story of cellular immunity. In fact, we tell a number of "separate" stories about the immunological response. There is the story about how antibodies are first formed and then used to illicit a rapid response when exposed to the same "intruder" again. There is the story of how the immune system responds to a bacterial, or similar, invasion. There is the story of how the immune system creates tolerance for the prevention of immunologically induced self-injury. There is the story of autoimmunity, whereby antibodies are formed against the body's own tissue, which will consequently be attacked. There is the story of anaphylaxis, an extreme overreaction of the body defence mechanism. There is the story of the complement system, which consists of at least 15 plasma proteins which interact sequentially, producing substances that mediate several functions of inflammation. A lot of stories in which different substances and pathways are described, but without any serious linking of the various stories or without any knowledge as to why and how the body chooses to follow that particular pathway on that particular occasion.
Returning to the acute phase response, the story we are particularly interested in, we know that there are many different cytokines (messengers) involved. One of the first cytokines to be released by the macrophages on detecting signs of injury or infection is known as interleukin-1ß (IL-1ß). It diffuses into the tissue surrounding the damaged cells, where it triggers a second wave of cytokines which cause other types of immune cells such as neutrophils and monocytes to migrate to the injured site. The IL-1ß released by the macrophages also enters the blood stream, where it is carried to the brain, but is prevented from entering the brain directly by a layer of cells known as the blood-brain barrier. It therefore adopts a more cunning route into the central nervous system. First, the IL-1ß molecules attach themselves to specially designed receptors on the surface of the cells in the blood-brain barrier. When these receptors are activated, a chain reaction is initiated that eventually leads to the manufacturing of a molecule known as prostaglandin E2, which, unlike IL-1ß, is capable of passing through the blood-brain barrier. When it enters the brain, prostaglandin E2 activates the receptors on both neurons and microglia (immune cells in the brain), which can then initiate the other components of the acute phase response: fever, lethargy, apathy, loss of appetite, anxiety, and increased sensitivity to pain in other areas of the body. But the story does not end there. Once inside the brain, prostaglandin E2 encourages the microglia to manufacture IL-1ß. The net result is that, although IL-1ß cannot cross the blood-brain barrier directly, a build-up of IL-1ß in the blood stream leads to a build-up of IL-1ß in the brain and the cerebrospinal fluid. To complete the cycle, the IL-1ß leads to further synthesis of prostaglandin E2 in the brain, which in turn augments the various components of sickness behaviour.
To compensate for the decreased supply of new calories caused by the loss of appetite, the body starts to unleash old calories that have been stored up for just such times of emergencies. These calories are stored in fat deposits around the body, but before the fat can be used as a source of energy it must be broken down into glucose. So another crucial component of the acute phase response is the secretion of glucocorticoids, which trigger the process of converting fat to glucose. The key glucocorticoid in humans is cortisol, which is released by the adrenal glands in response to a cascade of chemical signals initiated in the brain by IL-1ß. First, the IL-1ß stimulates the hypothalamus to secrete a chemical called corticotrophin releasing hormone (CRH). The CRH travels to the pituitary gland, just below the brain, where it triggers the release of another chemical called adrenocorticotrophic hormone (ACTH). Finally, the ACTH reaches the adrenal glands, which secrete the cortisol. Because of their close interconnections, the three anatomical structures involved in this chemical cascade are known collectively as the hypothalamo-pituitary-adrenal axis.
You do appreciate that the story presented here is a simplified version - nobody knows exactly what happens in all directions at any given moment in time - but it helps us to concentrate on that part of the story that we are particularly interested in. And here is a very interesting part of the story: the fight-flight response, which enables vertebrates to respond to large predators, evolved by co-opting the biological systems underlying the acute phase response. Both the innate immune response to infection and the fight-flight response to large predators activate the same immune-brain circuits. When a monkey or a human spots a lion moving rapidly towards them, for example, the hypothalamo-pituitary-adrenal axis is activated, just as it is by IL-1ß in the acute phase response. In both cases, the HPA axis responds with the same chemical cascade leading to the release of cortisol by the adrenal glands. This makes good sense, since cortisol breaks down the body's fat reserves into glucose that provides vital energy. It is of interest also to note that this whole system immediately reverses as soon as the danger has subsided. That may occur because the lion starts to run away from us, or because we all of the sudden recognise the "lion" as our favourite dog!
Problems I have with it
Let's go through the phases again.
The acute phase response, as is the fight-flight response, has to be an instantaneous response in order to keep you alive. The first thing that happens in damaged tissue or infection is a response from the macrophages, or the monocytes - this is not quite clear from the science. How many damaged cells, or how many bacteria, viruses or parasites, are required to trigger off this set of events? Macrophages and monocytes are floating around in the blood stream. What makes them aware of damaged tissue or foreign materials? Is it by sheer luck that they come across these? And if so, how do they get to damaged cells deep in an organ or structure, when they are mainly floating around in the blood? Whatever the answers to these questions, one thing looks likely: it is going to take time.
From here on, a number of different cells and a whole string of "messengers" are involved in the process. Let's follow just one line.
The macrophages, once they have located the problem, release IL-1ß which "diffuses into the tissues surrounding the damaged cells". This interleukin leaks from the macrophages into its outer-environment. In other words, for the time being, it remains local. After some time, it drifts into the blood stream. Via the blood stream it is taken up to the brain. That journey takes time. Of course, the blood stream will take the IL-1ß to all other places in the body too but as we have no information on what it might do there, we are better off totally ignoring that fact! If IL-1ß triggers off a second wave of cytokins which cause other immune cells to migrate to the site, why doesn't this happen anywhere else in the body whilst IL-1ß is travelling throughout the whole body? And furthermore, why isn't IL-1ß picked up by any of the elimination systems it travels past? How do the kidneys or the liver know when a molecule is needed or obsolete?
Now IL-1ß arrives at the brain, but finds that it can't enter. It attaches itself to specific receptors on the membrane of the blood-brain barrier. This is said to trigger a chain reaction on the other side of the barrier, i.e. in the brain. How many IL-1ß molecules are needed in order to trigger this reaction? What is the proportion between the number of molecules attached to the outside and the extent of the reaction? What is the regulatory mechanism and what will stop it? Finding an appropriate receptor site, reading the message and performing the reaction on the other side surely, all of that takes time.
One of the responses from the brain is to produce prostaglandin E2. Producing something in response to a direct order surely will take time.
Prostaglandin E2 is now capable of pushing through the blood-brain barrier. Passing through a check point surely takes time.
Once inside the brain prostaglandin E2 has to find very specific receptors on two different cells, the neurons and the microglia. Once this has been done, the other aspects of the acute phase response are put in motion. How many molecules of prostaglandin E2 are required to illicit such a response? How is the response, once it has been triggered, controlled? For the nervous cells to carry out these instructions to put in place "loss of appetite, fever, lethargy and increased sensitivity to pain in other parts of the body", is surely going to take time.
Also, prostaglandin is now encouraging the microglia to produce IL-1ß. This production of material in response to a very specific order must take time.
Oh nearly forgot, IL-1ß also travels to the hypothalamus, a particular part of the brain. This journey must take time. Once there, it stimulates the hypothalamus to produce the corticothrophin releasing hormone (CRH). This hormone travels to the pituitary gland, which is on the outskirts of the brain. This journey must take time. Do all these molecules know exactly where to travel to? If so, how? Otherwise, what happens to all the stuff that goes astray? And aren't we lucky that nowhere else except where it is required, tissues exist that possibly could respond to these drifters?
In the pituitary gland the CRH stimulates the production of the adrenocorticothrophic hormone (ACTH). Surely, the production of this must take time.
The ACTH is now released into the blood stream. Don't ask how? Are we now all of the sudden outside the blood-brain barrier? How did that happen; we didn't have the same fuss coming out as we had going in, did we? Via the blood the ACTH travels to the adrenal glands. Well, in fact, of course, it travels anywhere and everywhere in the body. Why is it only the adrenal glands that recognise this molecule? How does a cell that is part of a gland, and can't move, make contact with a single molecule that happens to be floating by in the blood stream? How many molecules are needed to trigger the response? How will the manufacturing and the amount required be regulated? The journey must have taken time.
The adrenal gland now produces cortisol. That production must take time.
Now you are ready for that lion that is running towards you. And guess what, if it turns out not to be a lion, you will turn this whole mechanism off straightaway and all the effects will be immediately reversed.
How much time do you reckon that will take?
And There is More
The main questions these theories throw up are about the time consumed in all these chemical reactions as well as the time spent travelling, and the very precision of the connections made. Don't forget that all of this can be switch off and on in a blink of an eye.
However, when we look around we find that there is more evidence we need to consider if we want to have a better understanding of the functioning of our body.
This leads to two serious consequences. One is the fact that somehow there must be a way that each cell has a direct line to our mind. A thought is not a physical thing until a cell produces something to make it physical. Yet, somehow the thought is "captured" by each and every cell and it is this thought that tells the cell what to do. Or in other words, a non-physical thing is heard and read by all cells and they react exactly to what is the essence of that non-physical entity. This must mean that all cells are highly sensitive to "a mood", to "something in the air", to "an atmosphere", "a sense of" or "an energetic alteration". As the mind changes, so does the function of each and every cell in the body; and only according to the state the mind is in. Be happy and all your cells are happy. Be angry and tense and all your cells are angry and tense. From the moment you think something is doing you good, it is. When you think something is damaging you, it is. It is the thought that provokes the effect, not the substance or the situation.
And secondly, it means that the immediate cell reaction we see is organised by the cell itself, producing all required attributes itself. Once these chemicals, proteins, peptides, hormones, etc. have done their job they are discarded into the surrounding tissue and dumped into the blood stream. As a reaction of the cell's activity, not as the cause of, the levels of these substances within the surrounding tissues and the blood itself will now start to rise. Along the banks of these extensive waterways a variety of anti-pollution plants (glands, organs) are available, which identify specific materials and filter them out of the blood circulation. These materials now accumulate inside the glands where they are destroyed and the building blocks recycled. Hormones, enzymes, chemicals, etc. are not produced by glands but collected and destroyed by them.
Once we know that all cells have receptors for all chemicals the body will ever use, and is capable of making these chemicals, we can now understand why everything always has an effect on every part of the body. From the fight-flight response to the influence of stress or the effect of hearing bad news, the effects of every aspect of our life is immediately felt in every nook and cranny of the body.
And then there is the problem of the white blood cells of our immune system, the gallant defenders of the tissues. We have already asked questions about the time and very specific actions of these cells. If they are floating in the blood stream waiting for a call about some damage or invasion, how would that message "catch" these constantly moving targets, and how quickly would they be able to respond in adequate numbers?
It seems there are other problems relating to our white blood cells.
What does all this mean?
For over twenty years now scientists have proven that every cell in our body can produce any enzyme, hormone or protein it needs, including "messengers". At the same time, every cell in our body has receptors for all the messengers, so that it communicates with its immediate environment.
The rapid and very precise response of the body to any situation leads us to believe, in view of all that scientific evidence, that every cell of the body is capable of "picking up" energetic signals and respond immediately and precisely to it. Every cell of the body "listens out" for signals in the air, not unlike the human-made radio system. It registers what it "hears" by producing the appropriate chemicals, which in turn set off a chain reaction as a direct result of the energetic environment the cell, and the whole body, finds itself in.
These chemicals, enzymes, hormones, proteins, have a very short shelf-life and are washed away into the lymphatic fluid that surrounds each and every cell, and into the blood stream. They are excreted by the cell and are essentially cell waste. Here it drifts around until an organ, a gland, "recognises" the material through its own specific receptors, captures it and draws it out of the blood stream. Within the inner workings of each gland or organ the mechanism for dismantling the chemical and recycling the building materials such as small molecules and basic elements is put to work. The higher the blood concentration of the specific substance the harder the gland has to work. It may even become swollen under a high workload pressure!
Within this system we also know that each cell produces its own anti-invasion chemicals, such as interferon and the lytic enzymes. In case of damage to the tissue or the invasion of bacteria (see "The Origin of Germs") the surrounding cells start the clean up process by producing the enzymes needed for the destruction and disintegration of the failing tissue. The rubbish that is consequently produced is "bagged up" in various cell-like structures, each equipped with the appropriate enzymes to break down the specific material it is carrying. It is a mobile recycling unit on its way to the depot, the spleen and lymph nodes. Here the "bags" are totally disintegrated, broken down into its basic components and recycled.
The conclusion is that:
me crazy! But before you do, take a long and hard look at the available
research science. Don't be afraid to change your mind if you find that
the truth lies outside your long-standing, and widely endorsed, beliefs.
Home ... Video ... Basic Principles ... Ear Candling ... Literature ... Contact
All rights reserved