HOW TO USE THIS EXERCISE

Slide numbers given usually refer to those in the Virtual Microscope collection available on the College server.  You’ll find these in the folder labeled “PATHOLOGY” using the NDPView program from Olympus America, which must be installed on your laptop.  If you don’t have this program, it’s available free from Olympus America at the following URL:

http://www.olympusamerica.com/seg_section/seg_vm_downloads.asp

If you would like to have a set of these slides for your personal use, please see Dr Caceci for instructions on how to create a “Virtual Slide Box” on your computer.  You’ll need quite a bit of drive space (about 70 Gb) for this, but it will enable you to use the collection off line.

Some slide numbers refer to those at Olympus America’s “Webslide Enterprise” server.  You will need to download and install Webslide Enterprise, available at the same site, to access this vast collection.  The WE collection can be searched by keyword, collection name, and slide number: all you need to do to find the slide referred to is to enter the number as give in the Search box and WE will pull it up for you.  The WE collection will not run off line, you must have a high-speed connection to the Web to access it.

Neither of these programs run on MacIntosh computers.  This is beyond my control: Olympus America simply doesn’t write software for Macs due to the small number of them in use compared to PC’s.  I have been told (but can’t verify) that “WebSlide NetViewer Active X” will run on Macs, and it’s also a free download.  Whether it gives access to the entire collection of slide I don’t know.

This exercise is “Version 1.0” and any omissions, errors, typos, etc. are my fault.  I will appreciate any corrections or comments you may have, please send them to me at doctorc@vt.edu and I’ll look into them.


OBJECTIVES FOR THIS EXERCISE

After completing this exercise the student will be able to:


READING ASSIGNMENT:

Kumar, Abbas, & Fausto.  Pathologic Basis of Disease Chapter 2 pp 47-86.


INFLAMMATION

Inflammation is the term used to describe the response of tissue to injury.  Its purpose is to destroy (or at the very least limit) the injurious stimulus, and to begin the process of healing.  Inflammation is a function of the connective tissues, and the immune system (which share a number of cell types in common).  The cells of the CT and the immune response all have specific roles to play in the process: consequently there’s a predictable sequence of events.  Based on the cell types and other tissue structural features observed, the pathologist can estimate quite accurately the stage the inflammation has reached.

ACUTE VERSUS CHRONIC INFLAMMATION

An inflammatory response to some insult begins acutely, that is, within seconds to a couple of hours.  It may resolve itself in a fairly short time, or it may complete the various stages of the acute phase and grade over into being a chronic condition.  The boundary between the two in terms of time isn’t hard and fast: but as a general rule, if an inflammation hasn’t resolved itself in a day or two it can be considered chronic.  Chronic inflammations can last a very long time—years, perhaps—but even they may in time resolve, with restoration and/or repair taking place. 

We’ll first consider the events and cell types involved in the acute process: and then look at what happens when inflammation doesn’t resolve and transitions to the chronic state.

One thing that must be stressed is that inflammation is a “good thing,” as Martha Stewart might put it (if she were a physician).  The goal of inflammation is restoration of normal tissue architecture and function, and in some cases that’s exactly what happens.  If because of circumstances complete restoration can’t take place, then the next best thing is repair, with some loss of function but elimination of the offending stimulus.  (As will be obvious from this, “restoration” and “repair” aren’t quite the same thing.)

Thus, when considering what (if anything) to do about an inflammation site, the physician has to keep in mind that Nature knows what it’s doing, and that the doctor’s role is to help Nature do it.  As “The Father of Surgery” Ambroise Paré humbly noted, Je le pansai, Dieu le guérit” (“I bandaged him: God healed him.”)  Managing inflammation optimally doesn’t mean suppressing it entirely; while today there are powerful anti-inflammatory drugs available, they may sometimes do more harm than good, if the inflammation is doing what it’s supposed to do.


WHAT CAUSES INFLAMMATION?

Dead cells and cellular debris are powerful inflammatory stimuli: anything that injures cells and tissues to the point of necrosis causes an inflammatory response.  It can be the result of infection, of trauma, of ischemia, chemical injury, radiation, etc.  Regardless of the initial source of injury, the results are the same.  Inflammation is a process that occurs in response to any kind of necrosis—coagulative, liquefactive, and caseous, but not apoptosis. 


HALLMARKS OF INFLAMMATION

The Five Cardinal Signs of Inflammation

This whimsical picture was drawn for a 2002 review article in Nature by the Department of Medical Illustration at St Bartholomew’s College.

Read the Article Here

The classical signs of inflammation, as described by Celsus 2000+ years ago, are Heat (Calor), Redness (Rubor), Swelling (Tumor), and Pain (Dolor).  Later physicians added Loss of Function to the list.  These signs can all be explained by considering the sequence of events in acute inflammation.


SEQUENCE OF EVENTS AND THE CELLS INVOLVED

Acute inflammation develops over a period from a few seconds to a few hours, depending on the nature of the injurious stimulus and the severity of the damage it causes.  A complete inflammation response has three components: vascular dilation, increased vascular permeability, and neutrophil activation/migration These are all interdependent processes.  Note well that inflammation is a connective tissue phenomenon, and that the cells and tissues involved are those of CT.

Vascular dilation occurs very rapidly (and may be preceded by a very, very brief constriction of arterioles).  Within seconds of tissue damage, arterioles dilate, increasing the flow of blood into the injured area.  This dilation enlarges the gaps between adjacent endothelial cells in the capillaries being fed by those arterioles and they become “leaky.”

As the diameter of the capillaries increases the flow of blood slows:  the increased leakiness of the walls allows fluid to move from the interior of the capillary into the surrounding extravascular spaces.  This accounts for the swelling (“tumor”): fluid moving into the interstices of the CT separates the fibers.  The escape of fluid into the extravascular space is seen as edema. The increased flow of blood also accounts for “calor”: blood carries heat in its fluid phase, and the increased flow brings heat with it, raising the temperature in the inflamed area.

Slowing of the flow causes neutrophils in the circulation to come into contact with the endothelium (“margination”).  Neutrophils have adhesion molecules on their surfaces that cause them to bind to receptors on the endothelium, and adhere.  Once adherent to the wall of the vessel, they extravasate to the CT spaces, as the “first responder” cells attacking the injurious material.  A preponderance of neutrophils is a mark that the response is in its early stages.  Neutrophil activity releases cytokines that attract more neutrophils other cellular participants in the response.

The image above is from Slide 75, demonstrating early events in acute inflammation.  It’s a section through the ear of a rabbit, which has had an injection of turpentine on one side but not the other.  The injection site is the lower part of the field.  Note that the spaces in the connective tissue are greatly enlarged by the movement of the fluid phase of blood into them: this edema occurs quickly in this type of chemical irritation.  At closer magnification (below) you will be able to see the hyperemia response, the enlargement of small blood vessels and their engorgement with blood.  This slide was made approximately 6 hours after treatment.  Hyperemia is also present on the un-injected side.

At  high magnification you should be able to make out some places where neutrophils have marginated and possibly a place where diapedesis is occurring and the neutrophils are leaving the vascular compartment for the CT spaces.  Many neutrophils have left and are scattered in the CT spaces, and some other cell types (e.g., macrophages) are beginning to appear: but this response to insult is still in the early stages, so the predominant cell type seen is the neutrophil.

On Slide 74, you’ll see the situation after 40 hours.  Now the area of injection contains necrotic connective tissue surrounded by an intense inflammatory cell exudates.  Viable and necrotic neutrophils, mononuclear macrophages (some of which have phagocytized erythrocytes) outline the necrotic area.  Edema is still present.  There’s a fair amount of cellular debris (seen as nondescript bits of material in among the cells) which results from the breakdown of necrotic cells.  These remnants will be removed by macrophages as well.  This is still in the acute phase, but quite a bit of change has occurred in 34 hours. 

In time, this inflammation is probably going to resolve of its own accord, since the offending stimulus is being diluted by the fluid leaving the vessel. Once the need for large numbers of neutrophils has passed, the dominant cell type present will be the macrophage, which clean up the site and remove the necrotic material (a powerful inflammatory stimulus in and of itself).  As the process continues eventually the area will be restored to normal architecture. 

We’ll consider later what happens when an acute inflammatory response doesn’t resolve and becomes chronic: but first we need to examine the various modes by which acute inflammation manifests itself.


MODES OF ACUTE INFLAMMATION

There are several categories or modes of acute inflammation, generally discussed and classified in terms of the exudate that’s produced.  The dictionary definition of an “exudate” is the material, composed of serum, fibrin, and white blood cells that escapes from blood vessels into a superficial lesion or area of inflammation. 

We can discuss these modes as serous, fibrinous, and suppurative inflammation, but in point of fact all of these modes are manifestations of a spectrum of increased vascular permeability caused by inflammation.

Of these three, serous inflammation is the least severe form, with minimal increase in vascular permeability.  It happens in a setting of relatively mild inflammation. Only low molecular weight solutes and water are able to pass from plasma into the extravascular space, so serous exudate is characterized by very low levels of protein, presence of few cells, and a yellow, straw like color.  This is what we’ve seen in the chemically induced response described above.

Note that there’s a difference between an “exudate” and a “transudate.” An transudate is a low-protein fluid pushed into the interstitium under normal pressure through a vessel wall whose characteristics haven't been altered.  In other words, the normal movement of blood’s fluid phase under ordinary hydrostatic pressure alone is a transudation, not an exudation.  Exudates are high-protein fluids released only under the increased hydrostatic pressure and leakiness associated with inflammation.

SEROUS INFLAMMATION

The induced chemical injury seen in the skin below is a nice example of serous inflammation. Dilation of blood vessels, increased blood flow, and increased permeability of vessel walls allows a protein-rich fluid serous exudate to be forced out of the vessel by increased pressure and leakiness. The epidermal layer of the skin is avascular: only the underlying dermis has blood vessels, So the exudate collects in the CT spaces of the dermis.

Typical examples of inflammatory responses causing serous inflammation include blisters of the skin caused by chicken pox, herpes simplex virus, or burns.  The usual outcome of serous inflammation is that the exudate is re-absorbed into underlying blood vessels and the overlying epidermis will regenerate, restoring normal structure and function.

FIBRINOUS  INFLAMMATION

Fibrinous inflammation is a pattern seen in cases of more severe injury, that result in greater vascular permeability. Soluble fibrinogen, a high molecular weight plasma protein, can exit only through large defects in the blood vessel wall. A mild inflammatory stimulus, even though it elicits increased vascular permeability, normally doesn't allow such large materials to pass into the interstitium, but more extensive injury will do so. Fibrinogen is an essential component of the clotting reaction that occurs when blood vessels are damaged.  When it’s cleaved to form insoluble fibrin, it’s a vital part of stopping blood loss, it’s not supposed to happen under other circumstances. And when it does, significant issues can arise. 

A fibrinous exudate is characteristic of inflammation in body cavities such as pericardium and pleura. The extensive vascularization and the delicate nature of these structures mean that often there’s enough damage done to trigger the release of fibrinogen and a fibrinogen-to-fibrin conversion external to the blood compartment. The result is fibrin in the interstitium. Histologically, fibrin appears as a eosinophilic meshwork of threads or as an amorphous coagulum.

Slide 60 is a case of   This is a case of pericarditis, inflammation of the pericardial sac around the heart. The secretory activity of the pericardium allows the heart to beat in a slick and essentially friction-free envelope. It is similar in structure to peritoneum, and as is true of any connective tissue structure, it’s well vascularized. In pericarditis the membranous envelope becomes inflamed. Here a fibrinous exudate has laid down fibrin threads in the interstitium. 

In this gross specimen serous fluid at the bottom of the pericardial cavity (arrow) is visible. The epicardial surface appears roughened, compared to its normal glistening appearance; this is due to the strands of pink-tan fibrin that have formed.

Most of the time the inflammation in these areas has a mixed serofibrinous character; i.e., it begins with a serous exudate which (due to its component of large-molecular weight fibrinogen) later becomes serofibrinous or fibrinous.  

The presence of fibrin may be enough to create sound when the layers of the pericardium move against each other, but sometimes the effusion of serous fluid is sufficiently large to obliterate it by separating the two layers of the pericardium.  In the extreme situation shown in the gross specimen here, a “pericardial friction rub” was audible through a stethoscope.

The microscopic appearance of this condition is seen here, in Webslide #MS_P074.  The exudate on the surface is shown enlarged in the inset.  On examining this slide you’ll note a considerable number of erythrocytes trapped in the mesh of fibrin threads as well.

SUPPURATIVE (PURULENT) INFLAMMATION

Suppurative or purulent inflammation is a mode characterized by the production of large amounts of purulent exudate or pus, a thick creamy fluid composed of intact and disintegrating neutrophils, within a background of fragmented and liquefied necrotic tissue elements. Neutrophilic lysosomes contain proteolytic enzymes to attack targets.  But neutrophils are “one shot” cells, which die after they’re used and have to be removed by macrophages. 

Here’s an example.  This is Slide 617, a case of purulent meningitis.  There are extensive accumulations of pus in the subarachnoid spaces.

Note the large numbers of neutrophils (recognizable by their multi-lobed nuclei) not only in the subarachnoid spaces, but in the blood vessels as well.  Macrophages are present, too, visible as fairly large mononucleated cells with eosinophilic cytoplasm and in some cases, lipofuscin and/or hemosiderin from breakdown of engulfed cells.

Suppurative inflammation is a characteristic response to certain types of bacteria that are “pyogenic” (pus producing), e.g., S. aureus, S.pneumoniae, etc. It should also be obvious that the response to this sort of agent can often do as much (or more) “collateral damage” to tissue as the invading bacteria can.  Systemically there will be effects from the release of intracellular products, cytokines, etc., often manifested as fever and other symptoms.

The morphology of suppurative inflammation is significantly altered by its position and the body’s ability to mount a resistance and to deal with it. An abscess is a localized collection of pus caused by suppurative inflammation in a tissue, usually in response to pyogenic bacteria. An abscess is formed when the inflammatory process fails to remove the causative agent and in an attempt to at least contain the damage, walls it off with CT.  This is the most common result of an infection with pyogenic bacteria.  As the island of necrotic tissue and neutrophils grows, a wall of fibrous tissue is formed around it in an endeavor to confine it. A good blood supply in the tissue ensures a nutrient supply for neutrophils which cross the barrier. This fibrous wall with an active blood supply that surrounds an abscess is called a pyogenic membrane.

Slide 264 shows an early stage in the formation of an abscess, before the formation of an encapsulating wall (actually, since this is in the cerebrum such a wall isn’t going to form, but we’ll deal with that later).  The bacterium has entered the brain tissue from the blood (via septic emboli)  and has formed small abscesses made up of collections of neutrophils,  associated with masses of tiny blue-staining bacterial organisms. 

Fibrinoid necrosis (diffuse pink-staining) of small arteries, and sometimes thromboemboli, are seen.  The microabscesses are seen in cortex and white matter, often adjacent to blood vessels.

If there’s a “good” place to have an abscess, it would be in some location that has the capacity to wall it off in connective tissue, and at the least contain the damage until it can be cleaned out.  This happens, for example, in the skin, usually in response to invasion by S. aureus.  The resulting inflammatory focus is called a “boil,” and is quite painful.  

Abscesses can occur in other locations.  Slide 946A is an example.  This encapsulated abscess is in the dura mater of the spinal cord (this lesion has progressed to the stage of being chronic).  This slide is stained with a connective tissue routine and demonstrates the extensive proliferation of the dura that has occurred to wall off the region of inflammation.  The CT is shot through with new blood vessels, which serve its needs and also bring in more inflammatory cells.  The pool of pus is isolated, more or less, but this is a space-filling lesion.  Its volume is sufficiently great, and the space in which it’s located sufficiently restricted (the overarching vertebral body has been removed) that inevitably it compresses the spinal cord proper.  While the inflammation isn’t in the cord itself, depending on the location of this abscess, any number of neurological deficits would be clinically evident.  If the abscess continues to grow, it may compress blood vessels serving the cord, causing ischemia, and hence probably necrosis in the cord.  Most decidedly not a “good thing.”

Some other terminology associated with suppurative or purulent inflammation is worth mentioning.  Phlegmon refers to spreading diffuse suppurative inflammation present in the loose connective tissue. Its margins are poorly defined. Phlegmon is rapidly progressive: some examples are cellulitis and acute appendicitis.  Empyema is an accumulation of pus within a body cavity, especially pleura.

FIBRINOPURULENT AND PURULENT-HEMORRHAGIC INFLAMMATION

Purulence can occur in concert with other modes of inflammation.  Slide 62 is an example of  fibrinopurulent inflammation in the lung.  These lesions are bacterially caused and feature regions of fibrinous exudate manifested by pink-staining filamentous material filling alveoli.  Hemorrhage is also present, thanks to damage to the delicate capillaries underlying the alveolar epithelium.  This damage is the result of the immune reaction mounted against the invading bacteria.  Pockets of blue-staining purulent exudates (note the neutrophils) are seen in small bronchi and bronchioles, and in some alveolar regions.

The presence of hemorrhage and fibrin has elicited a macrophage reaction: these cells are coming in to clean up the mess.

In the field above macrophages are in action.  The blood you see here isn’t hemorrhage, though: it’s in hyperemic capillaries between the alveoli.

Slide 120 is an example of purulent-hemorrhagic inflammation in the lung.  An extensive purulent pneumonia is present in alveoli and bronchial passages, with a hemorrhagic component as well.   This condition could be caused by bacterial invasion, but in this case it is an "inhalation pneumonia" due to aspiration of foreign matter.

As these images make clear, the accumulation of pus and blood in the lung impairs its function completely, and no gas exchange is going to take place.  How does this happen?  In this case the patient was under general anaesthesia and vomited: the foreign body shown is a piece of vomited food that was inhaled.  This is why patients are required to fast before surgery, and why inflatable cuffs are used to seal the airway. Even if it doesn’t kill, impairment of gas exchange for even a few hours can cause severe brain damage from hypoxia.  The gastric juices are powerfully acidic, and coupled with this foreign material, the reaction was severe, immediate, and in this case, fatal.  Inhalation pneumonia is seen fairly often in emergency rooms.

ULCERATIVE INFLAMMATION

Ulcerative inflammation is another pattern of acute inflammation, one that represents the "next step" in the progression beyond serous or suppurative inflammation. An ulcer is a local defect or excavation of the surface mucosa of an organ that is produced by the sloughing (shedding) of necrotic inflammatory tissue, with loss of surface mucosa.  An ulcer can be defined as a mucosal break greater than 3mm in diameter.

(Note that “ulceration” and “erosion” aren’t quite the same thing.  When speaking of damage to an epithelial sheet, “erosion” means a removal of epithelium, but not damage so great as to expose the underlying connective tissue.  Ulceration occurs when the surface of the involved organ has enough damage that the CT is exposed.)

Slide 139 demonstrates a recent esophageal ulcer, in this case caused by a viral infection. There’s a necrotizing inflammatory lesion producing a defect in the epithelial lined surface. Note the necrotic, sloughing epithelium, over the inflamed base of the ulcer and the dense eosinophilic (proteinaceous) edema fluid in the underlying submucosa.

The inflammatory cells in the CT under the ulcer base include many neutrophils,  macrophages, plasma cells, and lymphocytes, which should be identifiable under high magnification.  You may also note some few “giant cells” (see below), larger multinucleated macrophages that are indications that this lesion is approaching chronic status.  There is a good deal of fibrinous exudate present as well.  If this lesion heals, there will be a permanent fibrous (not fibrinous) scar formed at the site of the ulceration, and a deficit of function to the extent that the scar replaces the overlying epithelium.

 “PSEUDOMEMBRANOUS” INFLAMMATION

A variation of the theme of ulcerative inflammation is the pattern known as "pseudomembranous inflammation." This is rather rare, usually occurring in the mouth and pharynx (in diphtheria) , or in the gastrointestinal tract (in cases of antibiotic-associated colitis). Pseudomembranous inflammation is caused by some types of bacteria that produce potent exotoxins that kill the surface layer of mucosa.  The exposed underlying CT undergoes an intense acute inflammatory reaction, causing an outpouring of plasma and fibrinogen. A yellow-gray layer of coagulated fibrin (“pseudomembrane”) covers the surface of mucosa. It’s not a true anatomic membrane, and it can be scraped off during endoscopic examination, exposing a bleeding, ulcerated surface underneath it.  An example from a gross specimen is shown here.


CHRONIC INFLAMMATION

Chronic inflammation, by definition, lasts for weeks to months.  A wide variety of morphologic patterns is seen in chronic inflammation, and they may be mixed together.  The major characteristics of a chronic inflammatory state are on-going tissue damage (usually caused by the inflammatory cells themselves), the presence of a chronic inflammatory exudate, and fibrosis, i.e., the formation of a fibrous (not fibrinous) scar.

If an acute inflammation doesn’t resolve, it may progress to become a non-specific chronic one.  But a chronic inflammation often arises de novo as a result of exposure to certain injurious agents.  (A subset of the latter is granulomatous inflammation, whose morphology is specific and the result of a few specific causes.  We’ll examine this separately below.)

If the immune system’s response has been inadequate to remove the causative agent, a non-specific chronic inflammation may result.  In this situation there may be tissue damage, hallmarks of the acute inflammatory response, visible attempts at repair, and exudation present simultaneously.  The exudate in non-specific chronic inflammation is dominated not by the neutrophils typical of the acute stage, but by macrophages, lymphocytes, and plasma cells (though neutrophils are also present). 

Chronic inflammation is a situation representing an unhappy and unsettled pseudo-equilibrium: it may “flare up” and/or undergo periods of quiescence, smoldering sometimes for years at a time, alternating between repair or restoration and continuing destruction.  The classic example of this type of inflammation is the peptic ulcer of the stomach or duodenum, which affects millions of people in the US. (By some estimates, at least 10-15% of the total population has peptic ucler disease (PUD) at some time during life.)

In PUD mucosal necrosis results from the action of hydrochloric acid and pepsin in the digestive juices.  The layered, self-renewing defense against damage of the gastric mucosa ordinarily protects the blood vessels and connective tissues of the lamina propria and submucosa from injury by balancing losses against the rebuilding capability, but if something upsets the balance, ulceration occurs. It may be a one-time event with no long-term consequences; or there may be cyclical ulceration and repair, resulting in fibrosis of the underlying CT. 

Anything that impairs the process of healing can kick an acute inflammation into the becoming a non-specific chronic one.  Poor nutrition, poor circulation, immunosuppressive drugs, drug-resistant persistent infections, retained foreign bodies, etc. all will push the response into chronicity.  Factors favoring resolution include appropriate antibiotic and anti-inflammatory drugs, better nutrition, surgical removal of offending agents, etc.

Slide 6 demonstrates a chronic inflammation of the kidney.  This example of chronic interstitial nephritis demonstrates the features of a long-standing inflammatory state.  The damage is most prominent in the cortex, where it consists of lymphocytic infiltrates plus broad bands of scarring, with loss of nephrons.  Some dystrophic calcification may be visible.

In this low magnification view you’ll note a significant loss of renal corpuscles in the cortical area, and scattered areas of inflammation in the interstitium. The inflamed places  are visible as purplish cellular collections; these are also seen just under the capsule.  The architecture is recognizably that of a kidney but the tubules are degenerated and in many locations they’ve been replaced by scar tissue as attempts to repair the damage have taken place. Nephrons can’t regenerate so no “restoration” is possible: only ‘repair” by fibrosis.

At medium magnification the presence of inflammatory exudate in the interstitium is easily visible: several “dead” renal corpuscles and a good bit of interstitial sclerosis can also be seen.  The inset shows some areas of dystrophic calcification at a higher magnification.

Damage and loss of nephrons causes an inability to reclaim proteins from the urine forming in the remaining functional.  When the capacity to recover protein is severely depleted the accumulation of it is prone to form casts in the distal and collecting tubules. Casts may show up in the urine itself and can be seen in a urinalysis.  Proteinuria is a common symptom of progressing renal failure, whether or not casts are formed; but they’re seen in this field as collections of amorphous eosinophilic material (arrows).

The kidneys collectively have a huge amount of reserve functional capacity: when a chronic, persistent low-grade nephritis of this type sets in the loss of function can go un-noticed for a very long time, until the reserve capacity is exhausted, and end-stage renal failure is the inevitable consequence.

Slide 519 is another example of a chronic inflammation, this one showing a lymphocytic-histiocytic exudate in the mesentery.  Reactive lymph nodes are present, and a mesenteric fold rich in adipose tissue, blood vessels and nerves.  The chronic exudate contains lymphocytes, plasma cells, mononuclear histiocytes and macrophages, and pockets of neutrophils.  Focal regions of granulation tissue (fibrovascular proliferation) are also present. This last is an attempt to repair the damage: if the individual had survived, this would have resulted in fibrotic scarring of the mesentery, i.e., adhesions.  More will be said about granulation below.

In this low magnification image the lymph nodes are seen to have large numbers of active germinal centers in them: the surrounding mesentery is greatly inflamed and there’s a collection of inflammatory exudate in it, consisting of various cell types, which are better demonstrated at high magnification.

This image from Slide 519 shows at least three types of inflammatory cells: lymphocytes, their activated derivatives (plasma cells), and the ubiquitous macrophages.  The plasma cells are deeply basophilic thanks to their large amounts of rough endoplasmic reticulum: and frequently you can make out the Golgi apparatus in these cells as a clear cresentic area adjacent to the nucleus.  The macrophages are varied in appearance but generally are larger cells with a “baked potato shaped” nucleus and a rather eosinophilic cytoplasm.  They may contain ingested material, though this is better seen on Slide 27 (below).  Note the hyperemia (not hemorrhage) ongoing in this region of the mesentery because of the chronic inflammatory state.

Slide 27 is another example, this one of a chronically inflamed salivary gland.  At low magnification (above) you’ll be able to see the inflammatory cells en masse as deeply stained areas, and at high magnification (below) you can easily distinguish many macrophages.

The macrophage deserves some discussion.  These scavenger cells are derived from blood-borne monocytes, recruited into the area of inflammation by various chemotactic agents released by neutrophils and other participants in the immune response.  At the site they marginate and extravasate, as do neutrophils, and complete their differentiation into macrophages.

Macrophages (M) are “pleiomorphic,” i.e., they have varying appearances depending on their maturity and activity.  In the field above you see they have varying sizes, with the larger ones showing the characteristic “ground glass” appearance of the cytoplasm.  This is a manifestation of the presence of numerous intracellular lysosomes containing lytic enzymes. 

The cytoplasm of the macrophage, regardless of its stage of maturation, is fairly eosinophilic—much more so than that of plasma cells.  Some of the macrophages shown are of recent arrival: others have completed differentiation and become active, and can be seen to contain lipofuscin.  Lymphocytes (L) are also present in this field.

GRANULOMATOUS INFLAMMATION

A sub-type of chronic inflammation is the granuloma, which arises from a different mechanism than the non-specific type of chronic inflammatory response.  Granulomas are formed in response to certain specific stimuli, some immunological and some not.  They’re typically of very long standing and have quite characteristic cell types.  A key feature of granulomas is that the principal cell involved is the macrophage.

Low-toxicity organisms such as Treponema palladium, fungi, mycobacteria, some parasites, some hyperimmunity responses, a few intracellular viruses, and autoimmune conditions (e.g., lupus erythematosus) can produce granulomas.  There’s a special subset of granuloma that’s not immunologically based:  the foreign body granuloma, which forms when the immune system isn’t capable of removing an offending stimulus and continues to try to do so, often for a period of years at a time.  Inert materials (silicon, talc, asbestos) and other foreign bodies can produce this result, as we’ll see below.

The characteristic cell of the granuloma, of whatever form, is the macrophage in various forms, most especially in its “corporate” form, the  giant cell.  The giant cell is a multinucleated syncytium, a sort of conglomerate of macrophages that “join forces” to produce a “supermacrophage,” anywhere from 50 to 150 microns in diameter, far larger than any other cell in the region.  A granuloma can therefore be defined as a chronic inflammatory focus containing activated macrophages and giant cells.

Slide 55 demonstrates a granuloma in a lymph node.  The node is strikingly enlarged and its architecture is altered due to infection by a fungus.  This is an example of “granulomatous lymphadenitis.”  The granulomas themselves are masses of epithelioid cells (enlarged, active macrophages with pink-staining cytoplasm), multinucleated giant cells and lymphocytes. 

The round fungi with refractile cell walls are present in the multinucleated giant or epithelioid cells. The normal architecture of the node has been completely obliterated by the granulomatous inflammation.  A few remnants of normal lymph node structures are visible at the periphery but almost the entire interior volume has been taken over.

In the medium magnification image below the giant cells are visible and indicated by arrows.  The inset shows one at 400x.  Note the numerous nuclei, which in this type of giant cell (the Langhans giant cell) are distributed peripherally.  These cells arise by fusion of mononucleated precursors, i.e., macrophages, many of which are also in evidence, as are lymphocytes.

The causative agent in this example was a fungal organism.  Fungi have a capsule of polysaccharide material immune to any normal lytic enzyme produced by mammals, so clearing a fungal infection is a very, very difficult—often impossible—task for the body to perform.  Nothing produced by any form of macrophage, even a giant cell, is effective in dissolving the capsule.  Below is an image of several of these invading fungi; the one in the center has actually been engulfed by a giant cell, but it’s completely untouched.  Fungal infections require special drugs to treat, and are remarkably refractory even then.

Some specific bacterial infections also produce granulomatous inflammation, of which the classic example is tuberculosis, caused by infection with Mycobacterium tuberculosis.  This organism (and a few others) will produce a condition of caseous necrosis; the stereotypical lesion of this disease is the caseating granuloma whose center is composed of caseous necrotic material, surrounded by epithelioid macrophages and giant cells.

Here’s an example of this, from Slide 56. The inset in this image shows an area of necrotic material, inflammatory cells, and debris, with numerous giant cells present.  This particular caseating granuloma is in a lymph node, but tuberculosis can settle in many other organs such as the lung, kidney, or bone.  The open areas in the low-power view are regions of dystrophic calcification.

FOREIGN BODY GRANULOMAS

As the name implies, these granulomas form in response to the presence of exogenous indigestible materials. Typical examples include surgical suture material, splinters of wood, talc particles, parasite ovae and larvae, etc. Foreign body granulomas are usually notable for the presence of numerous "giant cells," essentially syncytial phagocytes; within them it is often possible to identify the causative material. Such cells, when formed in response to the inflammatory presence of a foreign material, are called "foreign body giant cells."  They differ from the Langhans giant cell in that their nuclei are randomly scattered in the merged cytoplasm.

Slide 76 is a nice example of an iatrogenic foreign body granuloma: it’s a bit of skeletal muscle in which silk sutures were placed 19 days before collection of the specimen.  The suture material is quite indigestible: silk is a β-pleated sheet protein not accessible to any normal proteases, hence immune from attack.  Note that there are multinucleated giant cells here and there and considerable  surrounding fibrosis.  In one region, pus is present around the suture. 

This higher magnification view shows the accumulation of pus.  A “frustrated” giant cell is at upper right of this accumulation: another is shown in the inset.

THE DIFFERENCE BETWEEN "GRANULATION TISSUE" AND "GRANULOMATOUS INFLAMMATION"

A perennial source of confusion is the similarity of these two terms.  We’ve already defined a granuloma, which is an inflammatory area of long standing containing giant cells.  It’s entirely different from “granulation tissue,” which is an example of fibrovascular proliferation. Granulation tissue is a stage on the road to healing by scarring.  It contains many new small blood vessels, active collagen-forming fibroblasts, and mononuclear cells in an edematous extracellular matrix.  Formation of granulation tissue is part of the repair response.


ORGANIZATION, RESOLUTION AND REPAIR

Restoration of normal architecture and function is the goal of inflammation.  Sometimes this is possible, sometimes it isn’t: it depends on what organ and tissues are affected.  Often the best that can be done is to “fill in the hole” with scar tissue, but sometimes the organ is capable of complete recovery once the inflammation is brought under control.

Slide 88 is an example of “organizing,” the process of converting a fibrinous exudate to collagenous scar tissue.  This is from a chronically inflamed joint (chronic synovitis) that has accumulated a good deal of fibrin as a “base” for this process.  Fibrinolysis by macrophages is occurring in the interior of the joint space while simultaneously invasion of granulation tissue (fibrovascular proliferation) is taking place from the inner lining of the joint capsule. 

The result of this process is a greatly thickened and probably less flexible joint capsule, which is probably going to limit the range of motion of this joint.

One organ that can complete the process of restoration of normal structure and function  (assuming that things haven’t gone too far) is the lung.  It contains within it cells that are capable of regenerating new epithelium, and under the right conditions it will heal completely.

Slide 119 shows the first stages of this process.  This is a case of chronic fibrinous pneumonia, beginning the stage of resolution. Alveolar spaces contain pink-staining fibrinous exudate, which has elicited a marked mononuclear macrophage response.  Macrophages are very numerous even in healthy lung, so they’re “on the spot” when needed and more can be recruited from monocyte precursors.  Here they’re actively phagocytizing the fibrin that’s formed, shown also in the inset.  Note that there are other cells present beside macrophages, but the macrophage is the dominant type.  Eventually, the fibrin will be removed, and normal structure of the lung restored.

Slide 1183 shows a healed gastric ulcer.  This low magnification image will allow you to orient yourself as to the mucosal surface of this section.  At approximately the mid-point there’s a large region of tissue loss extending to the submucosa, with a maturing granulation tissue at the base of the defect. 

This specimen shows healing of an ulcer, without regeneration of the normal tissue.  The granulation tissue extends into the muscularis propria.  A second ulcerated lesion, at a margin of the section, has marked chronic active inflammation, extending from the ulcerated mucosa through the submucosa.  Mononuclear cells, granulation tissue and neutrophils are present, indicating ongoing insult in this region.

This specimen comes from the glandular region of the stomach: once the healing is complete, the normal gland activity in that region will be lost because the proliferation of connective tissue replaced the functional glandular material: but the wall will remain intact.

Slide 521 is an example of healing in the pancreas and nearby mesentery, from a case of chronic pancreatitis. It shows a region of peripancreatic fat necrosis (compare with Slide 146).  Regions of fat necrosis and associated neutrophilic and macrophage infiltration are surrounded by granulation tissue made up of proliferating capillaries and fibroblasts.

This type of repair in the mesenteries can cause problems.  Granulation tissue progresses eventually to form a scar.  The normally slick and delicate coverings of the organs take on a firmer character thanks to the presence of so much collagen: and they will be connected to each other by the fibrous bands of collagen, forming adhesions.  Adhesions may restrict the normal movement of viscera over each other and impair ordinary functions such as bowel peristalsis, etc.  Adhesions are a common and more or less unavoidable consequence of abdominal surgeries: even if sterility is maintained and post-operative antibiotics are used to prevent any possibility of bacterial infection, the physical injury to the tissue is in and of itself inflammatory and adhesions are produced by the healing process itself.

Some tissues have limited or no capacity for restoration of normal structure and function.  Among these are some forms of muscular tissue, most especially cardiac muscle.  Slide 1182 shows a myocardial infarct that’s well advanced into the only “repair” possible to it, which is to proliferate scar tissue to connect the surviving myocytes.  Necrotic myocardium can’t regenerate at all so it has to be replaced by granulation tissue.  This process is a stage on the way to scar formation.

This damage is due to ischemia and anoxia that kills off the sensitive myocardial cells.  Those that are in the regions served by the blocked arteriole(s) die: those that aren’t survive, creating the pattern shown here.  Interspersed with areas of surviving myocardium whose blood supply wasn’t affected by the clot(s) are regions where the necrosis has triggered the inflammation now resolving by granulation.

This patient has suffered what’s commonly called a ‘heart attack,” and while he or she may survive it, it will be with some loss of function. 

At high magnification you can see the “edge” of the advancing granulation tissue: newly formed capillaries and active, basophilic fibroblasts are present, the latter forming new collagen fibers which in time will be anchored to the surviving myocardium, tying the undamaged areas together.  This heart will never regain the lost contractile force that those dead myocytes contributed to its function.