MODULE 3

INFLAMMATION & TISSUE REPAIR

PARKLAND COLLEGE

Natural Sciences Department

Champaign, IL

INSTRUCTOR: John MooreTHE BIG PICTURE

A functioning immune system is very much like an ongoing military battle. Some conflicts are major, and require all of the immune capabilities available. Others are simply minor skirmishes, needing only a squad instead of a battalion. In the armamentarium of the human body, the inflammatory response is often used for such small conflicts. As such, it is usually a very useful response -- for it brings additional blood, nutrients, and immune cells to the damaged region of the body. When the body finds it necessary to remove the dead and wounded following a battle, as is the case in real military battles, the immune system is called on once again. This is then followed by repair of the area and return to normal functioning (or as close to normal as possible).

This module will introduce you to the inflammatory response from both the beneficial, and the detrimental point of view. We will then continue on to the process of tissue repair/wound healing.

I. INFLAMMATORY RESPONSE - Etiology

Inflammation can be broadly defined as the response of a vascular tissue to injury. While the details will be discussed later in this module, it is important to realize initially that inflammation is, in fact, a beneficial process much of the time -- it brings additional blood to the injured tissue. As is the case with many things in physiology and medicine, inflammation can also be a two-edged sword -- for when it occurs in excess, it can be harmful to the tissues.

Tissues exhibiting the inflammatory response show varying degrees of the four cardinal signs of inflammation:

bulletredness
bulletwarmth
bulletswelling
bulletpain

Many in clinical fields add a fifth sign -- loss of function. The following is a brief overview of the inflammatory process. (Read Chapter 2 in your text for further details.)

 

Most authors break down inflammation into a hemodynamic component, and a cellular component. The hemodynamic component can be summarized as follows:

1) vasoconstriction -- occurs for a brief period of time following the initial tissue insult.

2) hyperemia -- increased blood flow to the area due to vasodilation. It is this increased flow of blood to the area that causes both the redness (L. rubor) and warmth (L. calor).  The clinical term most commonly used to describe the redness that results from the hyperemia is erythema.

3) increased capillary permeability -- this allows serum/plasma to exit the capillaries into the tissues. Among other things, this causes interstitial dilution -- a beneficial effect when the original tissue damage was caused by some form of chemical agent or toxin. The dilution makes the agent less harmful to the remaining tissues. The increased permeability also allows antibodies and, as we shall see below, WBCs to enter the tissues. The overall loss of fluid into the interstitial compartment is responsible for the swelling (L. tumor) and a portion of the pain (L. dolor). The swelling that results also triggers a pain response -- thus causing the person to (hopefully) stop or decrease using the affected area. A rise in blood viscosity occurs secondarily to the fluid shift out of the vessels. The resulting stasis of blood, when occurring in the venules, can increase the capillary blood pressure and increase the rate of exudate formation.

Terminology: Authors sometimes disagree on terminology, and this is one such occasion. When the above described stasis and rise in capillary pressure occurs, the resultant increase in fluid out of the capillary is called a transudate. A strict definition of a transudate refers to the fluid loss being due to an increase in pressure within the vessel. This is in comparison to an exudate, which is said to be due to increased capillary permeability (i.e., the fenestrations have enlarged.) In actuality, the fluid loss starts as an exudate, and turns into a transudate. This is due to the fact that the initial fluid loss leads to an increase in blood viscosity, which causes venous stasis. The venous stasis leads to an increased back pressure, which then causes the transudate. Most authors, including the author of your text, simply lump everything together and call it an exudate.

As the blood viscosity increases, the cellular component of the inflammatory response comes into play. The initial WBCs at the scene are the neutrophils, due mainly to the fact that they are the predominant circulating white cell. Monocytes show up at a later time, and are known as macrophages once they have emigrated into the tissues. The components of the cellular stage can be summarized as follows:

bulletmargination -- this occurs as the high concentrations of leukocytes move towards and adhere to the vessel walls in the area of the injury. As they adhere to the vessel, they flatten out and give the appearance of "cobblestones". This process is also known by the term pavementing.
bulletemigration -- occurs when the leukocytes then move along the capillary wall until a cellular junction is reached, at which point they actively leave the vessel in an ameba-like manner. (If RBCs leave the vessel due to increased pressure, this is known as diapedesis.)
bulletphagocytosis -- this is the process of "cell eating" done by the phagocytes present in the injured area. Bacteria, fungi, cellular debris, and immune complexes can be removed via this route. (The accumulation of defense cells, bacteria, and cellular debris is commonly known as pus.)
bulletchemotaxis -- this process is the attraction of various phagocytes to the inflamed tissue. The "attractant" is known as a chemotactic agent, which often includes some of the same chemical mediators (see below) involved in the initial stages of the inflammatory response.


The one question that is not answered by the above information is, "What causes all of this to happen?" The definition of inflammation mentions that it is all due to tissue damage. The real question, then, must be, "How does the tissue damage cause the hemodynamic and cellular changes seen in the inflammatory response?" The answer lies with a group of compounds known collectively as chemical mediators. As we shall see, these chemicals are key players in driving both stages of the inflammatory process.

Although there are many different chemical mediators, for the purpose of introduction and explanation, we shall concentrate on only two of them -- prostaglandins and histamine. Both are released when tissue damage occurs, although the amount of each released is variable. For example, tissue damage due to allergic reactions releases a far greater amount of histamine than it does prostaglandins. (We will delve into this in greater detail in the section on allergic reactions and anaphylaxis.)

Both histamine and certain prostaglandins (there are many different groups of prostaglandins -- some having little or no influence on inflammation) act to trigger both vasodilation and increased capillary permeability. The result is the hyperemia and fluid shift that was mentioned previously. In addition, certain of the prostaglandins have a direct effect on nerve endings in the tissues, resulting in pain above and beyond that caused by the tissue swelling.  (Interestingly, histamines do not generally initiate pain signals in neurons.  Hence, most allergic-type reactions are not terribly painful.)

II. INFLAMMATORY EXUDATES

As previously mentioned, the increased capillary permeability leads to a fluid shift from the vascular compartment to the interstitial compartment. These fluids, known as exudates, can have a quite varied composition. This is due to a) the degree of enlargement of the fenestrations in the capillaries, and b) factors influencing the exudate after it has left the vessel.

The major categories of exudates are listed below. Bear in mind that these are often not totally separate entities, i.e., it is quite possible to have combinations such as a fibro-purulent exudate.

serous -- a serous exudate occurs when only fluid escapes from the vessel. There are no proteins in the fluid. The fluid in a blister is a good example of a serous exudate.

fibrinous -- when the fenestrations are somewhat larger, some of the clotting proteins can escape along with the fluid. This results in an exudate that can form adhesions in the tissues. (Adhesions are areas where the tissue is literally "glued" together by the fibrinous mesh formed!)

purulent -- this exudate contains leukocytes and various types of cellular debris (a.k.a. pus).

hemorrhagic -- this exudate contains red blood cells.

CLINICAL NOTES: As mentioned previously, the inflammatory response CAN be , in the least - painful, and in the worst situation - harmful. It is during these "worst-case" situations that the various anti-inflammatory drugs can be used to eliminate or diminish the reaction. As we will mention later, some of the most potent anti-inflammatory drugs are the various corticosteroids. While acting quickly and in a powerful manner, these medications also have profound side-effects - with one of the most important being suppression of the immune system and wound healing. Because of these side-effects, various intermediate medications have come into use. While they are not as powerful as the corticosteroids, they also do not have as many side-effects. Many of these medications are grouped under the acronym NSAID - for non-steroidal anti-inflammatory drugs.

III. CHRONIC INFLAMMATION

While the majority of inflammations are of the acute form, some do progress into chronic states. These chronic conditions can affect many of the tissues and systems of the body. The common suffix used to describe an inflammatory condition is itis, e.g., bronchitis, appendicitis, sinusitis, arthritis, etc. (Note that in many cases, the tissue damage leading to the inflammation is, in fact, caused by an ongoing infection in the area. However, many inflammations can occur with absolutely no infection being present.) The types listed below are somewhat special in that they result in discrete areas of the body being walled off as a protective mechanism.

granulomatous inflammation -- in this condition, a "wall" of macrophages, fibroblasts, and connective tissue surrounds the triggering agent -- often an inorganic foreign body. Once formed, the granuloma can remain for life. (Just as an oyster forms a pearl around an irritating object such as a grain of sand, so the body forms a granuloma around foreign objects.)

CLINICAL NOTES: Some granulomas that form near the surface of the body will "float" to the surface over time. As an example, for years following the Vietnam war, clinicians were seeing patients with shrapnel granulomas that were migrating to the surface of the skin.

Historically, one of the major problems with the old talcum powder coated surgical gloves was that the patients often developed talcum powder granulomas at, and around, the surgical site. (Recall that talcum powder is a mineral (inorganic), and therefore not "digestible" by macrophages. Current "powdered" gloves use an organic based powder that does not generally cause granulomas.)

Currently, clinicians are seeing granuloma related problems with the NorplantTM birth control capsules. The resulting granulomas are, in some cases, making it quite difficult to remove the capsules.  When the granulomas are thick enough, there is also the possibility that diffusion of the encapsulated steroids might be impaired.

Although they are often similar in external appearance, granulomas should not be confused with abscesses. While an abscess is a walled off region, there is usually some form of active infectious process occurring within it. On one hand, the abscess wall decreases the tendency of the infection to spread. At the same time, it also makes it difficult for antibiotics to get to the site. This is why abscesses must often be lanced and drained before they can be effectively treated. When occurring in a tissue with low vascularity, there is often little or no inflammation around the site, leading to the name of cold abscess.

Boils, furuncles, and carbuncles are all terms for various types of abscesses that originate, or are associated with, hair follicles of the skin. Abscesses of the distal end of the finger are known as either felons or whitlows.

 

CLINICAL NOTES:  One of the more common encountered clinically condition involving chronic inflammation is Ulcerative Colitis (which will be covered in more detail in the module in the GI system.)  It is interesting to note that some patients with UC find relief by wearing the "nicotine patches" used for cessation of smoking.  The mechanism is not understood, but one possibility is that nicotine, being a potent vaso-constrictor, is diminishing the increased blood flow associated with the inflammatory response.  This also may explain the fact that UC is a condition found predominantly on non-smokers!



IV. SYSTEMIC SIGNS OF INFLAMMATION

In addition to the local signs of inflammation, systemic signs of inflammation often occur. While rather non-specific in their diagnostic usefulness, they do assist in obtaining the first stages of a differential diagnosis. The three most useful systemic signs are:

leukocytosis -- this elevation of the white cell count is usually associated with an ongoing infection in the body. (And the infection is what is causing the tissue damage associated with the inflammation.)

ESR -- the erythrocyte sedimentation rate is a non-specific test associated with conditions of both anemia and inflammation. The rate at which the erythrocytes settle from the blood is increased in cases of major inflammatory conditions.

fever -- some of the prostaglandins released as chemical mediators are capable of elevating the hypothalamic "set point" for body temperature. This elevation is known as fever.  Do note that, unlike conditions such as heat stroke, the hypothalamus is functioning normally during fever - it is simply "set" at a new, higher value.

CLINICAL NOTES: As is the case with inflammation, fever is a beneficial response -- as long as it does not occur to excess. Many bodily functions, including the ability to fight off foreign organisms invading the body, are increased when body temperature increases. For each 1oF increase in body temperature, there is an increase in heart rate of between 8 - 10 beats per minute, and an overall increase in metabolic rate of 7 - 10 %. Both interferon and the various macrophages of the immune system function better at increased temperature. Severe increase in body temperature, such as that of a major fever or hyperthermia, IS capable of causing profound damage to areas such as the brain.

V. TISSUE HEALING

Once a tissue has been injured, the healing process will begin. (Assuming, that is, that the injurious process has ceased.) The type of healing depends upon the type and degree of injury, and the type of tissue that was injured. Muscle and nerve tissue are amitotic, and cannot be replaced. (We will talk more about nerve regeneration in the module on the Nervous System. For now, simply realize that some injured neurons can regenerate portions of the cell.  Also, there is some evidence to suggest that "some" CNS neurons do, in fact, have a limited capacity for replication!) Conversely, when a healthy person loses a part of their liver, the liver can easily regenerate new cells to the point where the liver will appear relatively normal a year or so after the injury! The rate of tissue repair can be quite variable from organ to organ, and tissue to tissue. Even within the same organ, quite a degree of variability exists. Skin, for example, will exhibit two different rates of healing based on whether the injury has damaged just the epidermis, or has also included the dermis. Epidermis, being of ectodermal origin, heals far faster. Tissues of mesodermal origin, such as the dermis, heal at a much slower rate.

One of the most common ways that the body can "repair" itself is by way of scar tissue. Just as a repairman can use spackling compound to repair damage in a plaster wall, the body can generate scar tissue to fill in defects in the body. The following is a brief overview of the process of tissue repair via scar tissue formation. (Keep in mind that scars, although often thought of as those structures we see on the outside of the body, can also form in internal organs and tissues.)

Injury -- the organ or tissue is first injured by any of the methods previously mentioned.

Bleeding -- in most cases there will be bleeding into the wound site. This blood will eventually clot and, if on the external surface of the body, will dry to form a scab. This dried scab helps to prevent both fluid loss and invasion by external organisms.

Cellular infiltration -- the wound area will next be infiltrated by WBCs and by fibroblasts. The WBCs will attempt to eliminate any organisms that have entered through the injury site. The fibroblasts will eventually begin producing collagen fibers that will comprise the actual scar tissue. As the clot dissolves, the amount of scar tissue increases to replace it. The end result is that the damaged area is "filled in" with the collagen fibers of the scar tissue. Prior to the final scar tissue being formed, the area is a mass of both collagen fibers and blood vessels. This tissue is rather pink and granular in appearance, and is given the name granulation tissue.

CLINICAL NOTES: It must be noted that such a "repair" will result in some degree of lost function -- for the scar tissue will NOT be able to carry out the function of the tissue it is replacing. Following a myocardial infarction, the damaged area of the heart is replaced by scar tissue. If all other factors remain the same, that particular portion of the heart will not have the same contractile ability as it did before the infarction. An additional problem encountered in the heart is the fact that the scar tissue does not actively conduct electrical impulses, resulting in conduction dysfunctions following the infarction. Internal scar formation, many times in conjunction with fibrinous exudates from the injured region, can often result in tissues or organs "sticking" to each other -- a condition known as an adhesion. Such adhesions can lead to serious post-operative complications, occasionally requiring additional surgery to remove or "break" them.

In order to diminish the size of scars, clinicians use the concept of wound edge approximation. This refers to the practice of bringing the wound edges as close as possible to each other, and stabilizing them with sutures, staples, tape, or surgical glue. By doing so, much less scar tissue is necessary to "fill in" the wound site. This type of healing -- where living, viable tissue is in contact with similar tissue -- is known as healing by primary intention. Healing by secondary intention occurs when the wound is left "open", and a large amount of scar tissue is needed to repair the area or "bridge the gap".

Cauterization, while useful to control bleeding at an operative site, can actually slow the post-operative healing process. This is due to the fact that tissue macrophages must first eliminate all of the dead/charred tissue before true repair can begin. In other words, healing occurs most rapidly when live, vascular tissue is in contact with live, vascular tissue.

Once scar tissue has formed, it has a tendency to shrink or regress. In many cases this is good, for it pulls the wound together. However, when the scar tissue is in an area that requires movement or flexibility, severe problems can result. Such is often the case involving burn related scars of the thorax (with difficulty moving the ribs for breathing) and the hands (with difficulty moving the fingers as intended.)

 

 

 

VI. FACTORS INFLUENCING HEALING

As previously mentioned, different tissues "heal" in different ways, and at different rates. In addition, the following factors can have an influence on the healing process:

Age -- in general, healing rate diminishes with age. This is thought to occur due to a decrease in both vascularity of tissues, and the overall metabolic rate of the tissues - possibly correlated with diminishing levels of Growth Hormone.

Dehiscence -- in this condition, the healing site "breaks open". Although there are many causes, some of the most common are: excess movement by the patient, coughing, vomiting, straining during defecation, weakened tissues secondary to excessive steroid use, or increased pressure due to pus accumulation. Rarely, the person closing the wound did not take a big enough "bite" of tissue with the needle - resulting in the sutures not being fully anchored. To use the above mentioned terminology, dehiscence results in a loss of wound edge approximation.

Infection -- when present causes a decrease in the rate of healing.

Anti-inflammatory steroids -- although they DO decrease inflammation around the healing wound, they also SLOW the actual healing process.  Prolonged use will also weaken tissues.

Blood supply -- vascular tissues heal much more rapidly than less vascular tissue, e.g., bone will generally heal more quickly than cartilage.

Smoking -- relating to the previous topic, the vasoconstriction effect of the various chemicals in cigarette smoke cause all tissues to have a somewhat diminished blood flow.

CLINICAL NOTES: Many plastic/cosmetic surgeons try to dissuade older patients who smoke from having elective cosmetic surgery. They do so based on the poor healing characteristics of these patients.

VII. BONE HEALING

Although not covered in this course, it should be mentioned that bone healing is, in principle, very similar to soft issue healing. The major difference is that osteoblasts and osteoclasts actually form and reshape new bone at the site of the break. Your text has further information if you are interested.

VIII. NERVE REPAIR

As neurons are generally considered to be amitotic, they cannot be "replaced" once they die. (Remember, the neurons you were born with are the identical neurons you will die with -- minus those that die along the way!  So BE NICE to those neurons - they have to last a long time!)   Certain neurons, such as the myelinated neurons of the PNS, are often capable of axonal regeneration when injured. The newly regenerated axon "follows" the myelin sheath from the previous axon. This phenomenon also accounts for the fact that parts of the body that have been cleanly severed in various accidents can be surgically re-planted. A micro-vascular surgical team reattaches the vessels and nerves, at which time the neurons start their process of regeneration. Although individual variation is evident -- regeneration usually occurs at the rate of 1 mm/day. If the two ends of the nerve/sheath are not attached to each other in short order, infiltration of scar tissue will prevent regeneration from occurring.

 

                                                               

CLINICAL NOTES: As of the writing of this portion of the module, various news reports have come out stating that researchers have accomplished actual neuron replacement or regeneration in the CNS of research animals. 

Some of you may want to consider this as a term paper topic - IF you feel you can find enough newly published data. (HINT: check for the articles BEFORE you select the topic!)

RETURN TO OUTLINE            e-mail me

Contact instructor for TERM PAPER approval.