The Acute Inflammatory Response
First line of defense against an injury.
Inflammatory reaction is proportionate to the degree of tissue damage.
Blood vessels lead to “leakiness” of the vessels, such that fluid, chemicals and leukocytes can move into the tissue
Benefit of these changes is that the agent is (with luck) destroyed, and debris is removed to allow repair.
inflammation is a nonspecific response; not just initiated by infection, but by anything which causes tissue
TISSUE INJURY leads to INFLAMMATION
Inflammation develops, resolution and healing begins almost immediately, time taken to reach these endpoints
is extremely variable The separation of “inflammation” from “healing” is really an artificial, manmade
The process of acute inflammation has two major components. These are:
A. Vascular changes
vessels dilate to increase blood flow to the area
vessels become more permeable, to allow plasma proteins to leave the circulation and enter the injured site
B. Cellular response
Leukocytes leave the microcirculation and accumulate at the injured site
Vascular (blood vessels) changes occurring in inflammation occur in the microcirculation, the capillaries,
arterioles and venul.s
Become dilated (vasodilation) = is more blood in the area= redness, vessels become leaky, so fluid moves into the
tissue spaces = swelling.
1. Transient vasoconstriction, but this reaction is not very significant.
2. Active dilation of arterioles, capillaries and venules caused by the release of a variety of chemical mediators
from damaged and necrotic cells: vasoactive amines (histamine and serotonin), kinins, etc. Histamine,
released by mast cells is a derivative of the amino acid histadine; it has a myriad of effects within the body,
depending on tissue type and animal species. Generally, it causes capillary dilation.
Are found in greater concentration in the from damaged and necrotic cells: vasoactive amines (histamine and
serotonin), kinins, etc.
Contain membrane bound vacuoles (`granules' contain histamine). Injury to the surface of the mast cell leads to
`degranulation' of the mast cells, with ubsequent release of histamine.
- Only some of the capillaries within a tissue contain a stream of blood. - The precapillary sphincters of the remaining capillaries are closed, which causes much of the blood to pass through
the tissues via the “freeway” channels (directly from arterioles to venules).
- As you become more active, the precapillary sphincters open, and blood is diverted from these freeway channels to
perfuse the tissues in response to their increased metabolism. The dilation of arterioles also brings more blood
into the area.
- Inflammation is similar to this physiologic response, with arteriolar dilation bringing more blood into the area,
and more capillaries in the tissue containing blood. This increased flow of blood in the tissue is termed
hyperemia, and is the reason that the inflamed tissue looks red.
- The increased permeability of capillaries and venules (the leakiness) occurs initially because of a widening of the intercellular
junctions(the “pores”) between endothelial cells – the cells which make up the vessel wall . Remember that fluid normally leaves
the capillaries at the arteriolar end of the capillary bed under the influence of hydrostatic pressure, and returns to the vascular space
at the venular end of the capillary bed due to osmotic pressure. If the normally selectively permeable barrier of the
endothelium(which only allows small molecules to pass through) is damaged by inflammation, the spaces between endothelial
cells are much wider than normal, and increased amounts of fluid as well as larger molecules (proteins) will pass out of the vessels
and into the extravascular space, a process called exudation. This causes the swelling and accumulation of inflammatory exudate.
Acute inflammation is thus an important cause of localized edema
Increased vascular permeability is the result of more than the initial widening of intercellular gaps.
Causes of increased vascular permeability can be summarized:
The initial endothelial cell contraction, which widens intercellular junctions, is a transient process, occuring
primarily in venules. A more prolonged ‘retraction’ of endothelial cells [mediated by tumour necrosis factor (TNF)
and interleukin-1 (IL-1)] also occurs.
Direct injury to endothelium causes endothelial cell necrosis and detachment = leakage from vessels
O primarily after severe injuries (burns, infections)
Leukocyte-mediated endothelial injury:
O Leukocytes release proteolytic enzymes and toxic oxygen species which further endothelial cell injury and
O Transcytosis refers to fluid movement across endothelial cells via vesicles
Leakage from newly forming blood vessels
As fluid moves into the interstitial space, the blood becomes more viscid (“thicker”). This causes the flow of blood
to slow down, a process termed stasis.
Normal Capillary (left) versus Capillary in Acute Inflammation
Note widening of spaces between endothelial cells, swelling of endothelial cells, and increased blood flow within
the capillary. Inflammatory exudate – Exudation, the process of increased movement of fluid and larger molecules out of the
vasculature due to increased vascular permeability. The fluid which then forms in the tissues or at tissue surfaces is
What are three differences between a transudate and an exudate?
- exudate would be more like plasma in composition
- Transudates are basically an `ultrafiltrate’ of plasma–
- Increased permeability of the endothelium allows many plasma proteins (large molecules) to leave the vascular
space. immunoglobulins (antibodies), complement and fibrinogen–
- Large molecules from the plasma into the interstitium will decrease the osmotic pressure – swelling. the increased
tension in the tissues caused by fluid accumulation will tend to limit further exudation .
Exudates and transudates are formed under different circumstances (transudates form with normal vascular permeability, while
exudates form with increased vascular permeability :
Protein Content Low (<3g/dL) High (>3g/dL)
Various (albumin, globulins, fibrin)
Protein Types Mostly albumin
Numerous, often degenerate;
Cells Few, healthy neutrophils will often predominate
Appearance Clear, colorless Turbid, yellow/white, pink
Ascites: The accumulation of fluid in the peritoneal cavity, causing abdominal swelling.
Peritonitis: Inflammation of the peritoneum, typically caused by bacterial infection either via the blood or after
rupture of an abdominal organ.
- Appropriate treatments for these conditions might be very different; it is important to differentiate between these.
Differential Diagnosis:the process of differentiating between two or more conditions which share similar signs or symptoms.
Definitive Diagnosis:is obtained when physical signs and/or test results sufficiently fit a particular disease process to make
the practitioner positive of the patient’s diagnosis.
Transudate: Any fluid (solvent and solute) that has passed through a normal membrane, as a result of imbalanced
hydrostatic and osmotic forces; characteristically low in protein unless
Exudate: Any fluid that has exuded out of a tissue or its capillaries, because of injury or inflammation in which case it is
characteristically high in protein and white blood cells.
Hypoproteinemia decreased vascular oncotic pressure
What are the benefits of exudation? It “dilutes” any offending agent, it brings many defensive proteins into the
area, increases drainage of the area via the lymphatics. This lymphatic drainage takes agents to the local lymph
nodes, where a protective immune response is facilitated
Fibrin - Formed from the plasma precursor fibrinogen, which is a high-molecular-weight plasma protein synthesized by the
liver. Fibrinogen normally exists in an inactive form in the plasma, and contributes to plasma osmotic pressure
- Escapes from the capillaries when permeability is increased then converted to fibrin via tissue thrombin, which is
formed from tissue thromboplastin.
- Exists in a monomeric form, which is then acted on by a coagulation factor (Factor XIII) to produce a fibrillary
polymer which is insoluble– this is “fibrin”.
- In tissue sections, pink-staining meshwork in the interstitial spaces. It aids in localizing the inflammatory process,
and provides a meshwork to aid neutrophil movement.
“Shipping fever” lobar pneumonia caused by infection with the bacteria Mannheimia hemolytica.
- Abundant fibrin production, within the lung & pleural surface= adhesions between the pleura of the lung and that
lining the ribcage. Cattle which have been stressed by transportation and have a predisposing respiratory viral
Cellular Events: Leukocyte Recruitment & Activation
Acute inflammation is characterized by the active emigration of inflammatory cells from the blood into the area of tissue injury.
However, for inflammatory cells to enter an injured area, they must first be attracted to the area, attach themselves to the capillary
wall, then squeeze through or between the endothelial cells. The increased permeability of the capillaries favours this movement of
inflammatory cells from the blood into the tissue. I will discuss these processes in greater detail shortly, but first will introduce “the
The inflammatory cells
- white blood cells, or leukocytes
- From myeloid cell line, into the bloodstream when they are mature.
- The myeloid cell line has two “arms”, the mononuclear cells and the granulocytes
- mononuclear cells have a smoothly outlined, rounded nucleus (“round” cells)
- granulocytes have a multilobulated nucleus, contain cytoplasmic granule (polymorphonuclear leukocytes)
1) bone marrow is the primary site of differentiation for leukocytes, as well as red blood cells and platelets
2) one marrow-derived cells are actually derived from common precursors.
These cell lineages respond to a cocktail of different “cytokines”, “colony-stimulating factors”, and hormones to
up regulate or down regulate production of their mature forms (more on cytokines shortly).
Granulocytes (Neutrophil, basophil and the eosinophil)
Neutrophil has the greatest role in acute inflammation, and is the white blood cell seen in acute inflammation
- Neutrophils are actively motile, capable of phagocytosis, and contain enzymes which can degrade biologic material.
- The main function of the neutrophil is phagocytosis of microorganisms.
- Individuals with low neutrophil numbers or with defectively functioning neutrophils are at increased risk of infection.
Eosinophil: contain a different repertoire of enzymes and granules than neutrophils, are typically recruited to fight parasitic
diseases, and are often directly involved in hypersensitivity responses.
Mononuclear cells (lymphocytes, plasma cells, monocytes, and macrophages)
- greater role in the later stages of inflammation
- Antibody producing cells termed plasma cells.
- Monocytes are present in the blood, but are able to migrate into the tissues. - in the tissues they are termed macrophages
- ingest micro–organisms and also help “clean up” cellular debris. secreting substances such as endogenous pyrogen
and complement components .
1. Margination, Rolling and Adhesion of Leukocytes
- microvasculature dilates and becomes leaky in acute inflammation, the rate of blood flow within slows = normal laminar flow of
blood constituents within the vessels to become disordered, and white blood cells tend to move out toward the vessel wall as
opposed to flowing more centrally.
Margination increased contact between the leukocytes and the endothelium.
- marginated leukocytes ‘roll’ along the endothelial surface, sticking. Mediated by selectins, receptors expressed on both the leukocyte
and endothelial cell surfaces. These receptors are up-regulated after stimulation by a variety of inflammatory mediators.
Pavementing or Adhesion: the endothelial cells become “sticky”, the leukocytes tend to adhere to the vessel wall
Margination and Pavementing of Leukocytes
- Adhesion is mediated by integrins on the leukocyte surface, which interact with specific ligands on the endothelial cells.
Selectins – Select the leukocytes they want to marginate within the vessel!
Integrins – Integrate the leukocytes into the tissues!
2. Transmigration of neutrophils
- Adhered neutrophils leave the vessel by squeezing between the intercellular junctions, a process termed diapedesis.
- enlarged pore size of the endothelium (makes movement easier).
- They then pass through the basement membrane, by focally degrading them with secreted collagenases, and move into the tissue
spaces (also known as the interstitium). This process primarily occurs in venules in the systemic circulation. (See diagram below)
Diapedesis of Neutrophils
Diapedesis of Neutrophils
This movement of leukocytes through intercellular junctions is also facilitated by specific cell adhesion molecules. If you were to
look closely you could see the pavementing and diapedesis of neutrophils, the result of vascular changes occurring in acute
3. Chemotaxis Chemotaxis inflammatory cells are attracted to an area of injury by directional migration along a chemical concentration gradient.
- Chemical mediators of inflammation act as chemotactic signals to inflammatory cells; (C3a & C5a) leukotriene & cytokines.
- Chemotactic molecules bind to specific receptors on the leukocyte surfaces = increased intracellular calcium and triggering the
assembly of intracellular contractile elements.
- These contractile elements allow the leukocytes to move; by extending pseudopods. The chemotactic molecules also induce
4. Leukocyte Activation
- Leukocytes must be activated before they can use these effectors.
- The body has a variety of ways that it can recognize tissue injury and foreign invaders. the components of the acquired immune
system (antibodies) are designed to be able to identify a single molecule present on such foreign substances.
- Leukocytes themselves have a variety of surface receptors that will recognize common markers present on bacteria and other
pathogens (Pathogen-Associated Molecular Patterns/ PAMPs).
- Toll-like receptors, which recognize various bacterial, viral and fungal components. Recognition will activate the leukocytes and start
up the inflammatory response.
- Soluble and tissue molecules (the opsonins, discussed below) present normally can similarly bind foreign substances and indirectly
mediate leukocyte activation.
The initial activation of these leukocytes leads to several different changes, including:
o Up regulation of mechanisms for degradation and killing of microbes
o Production of inflammatory mediators
5. Phagocytosis & Pathogen Degradation
Phagocytosis: the process by which certain cells ingest and destroy particulate matter.
- First recognize and attach to the particle or agent; this recognition can either be nonspecific or specific, which occurs when the
particles/agent have been coated with antibody or complement factor 3b, a process termed opsonization (the IgG and C3b act as
Collectins, carbohydrate-binding lectins found in the plasma, also bind to microbial cell walls as opsonins. In turn, leucocytes have
specific receptors for IgG, complement, and collectins.
- Opsonization leads to enhanced phagocytosis. Early in acute inflammation, nonspecific phagocytosis will dominate, but as the immune
response develops, immune phagocytosis is more efficient.
- Recognition and binding of opsonized particles has occurred, the particle is engulfed by the phagocytic cell, forming a membrane-
bound vacuole within the phagocytes’ cytoplasm (the “phagosome”).
- Phagocytosis stimulates a sudden increase in the oxygen-dependent metabolism in the leukocytes, the end result of which is the
production of large quantities of reactive oxygen species.
- Killing of most pathogens is mediated by reactive oxygen species, by similar methods to those in which reactive oxygen species can
mediate cell injury and death.
- Pathogens are then further degraded by fusion of the phagosome with lysosomes, which release acid hydrolases and other enzymes
variably capable of killing and digesting the pathogens.
Mediators of Acute Inflammation
- Chemicals derived from either plasma or cells. - Plasma they exist as inactive precursors; activation occurs via the action of specific enzymes. The mediators
which are derived from cells are either pre-formed and stored in cytoplasmic granules, or formed when
- The chemical mediators exert their effects by binding to specific receptors on a variety of cells, and often they
lead to the release of further mediators.
- Very specific or widespread effects. Their function is generally tightly controlled, with many inherent ‘checks
and balances’ in the system.
1. Vasoactive amines – Histamine (released from mast cell granules) and serotonin (platelet aggregation)
cause vasodilation and increased permeability. Greatest role of the inflammatory mediators, cause the
immediate phase of the acute inflammatory response.
2. Plasma proteases – These plasma-derived factors share in their initial activation by Hageman factor
(Factor XII, introduced for its role in coagulation). Hageman factor (a protein) is synthesized in the liver,
and circulates in plasma in its inactive form; endothelial injury exposes substances which lead to its
activation to XIIa, which can in turn cleave a variety of protein substrates.
a) The Kinin system – Bradykinin, causes increased vascular permeability and also mediates pain. It is
produced from a precursor plasma protein via the action of the enzyme kallikrein; kallikrein in turn is produced
via the action of XIIa on an inactive plasma precursor, prekallikrein.
b) The coagulation cascade – thrombin activation and ultimately leads to the production of fibrin, can also be
initiated by XIIa. When fibrin is broken down, fibrinopeptides which are released can increase vascular
permeability, and are chemotactic for neutrophils. Thrombin also acts to enhance leukocyte adhesion to
c) The complement system –C5a and C3a, formed in the activation of complement, stimulate histamine
release from mast cells, thus increasing vascular permeability. C5a acts as a chemotactic agent and activator for
phagocytic cells, and C3b acts as an opsonin. C5a also activates the lipooxygenase pathway of arachidonic acid
metabolism. C3 and C5 are also activated by proteolytic enzymes found in inflammatory exudate; this amplifies
the influx of neutrophils to the inflammatory site.
Answer the following questions: (see p. 50-52, text)
1) Activated Hageman factor (XIIa) initiate’s which four systems that are involved in the inflammatory
2) Bradykinin, C3a and C5a are important mediators of:
3) C5a is an important mediator of cutaneous inflammation
4) Thrombin has several roles (three points)
3. Lysosomal constituents – Neutrophils generate toxic oxygen-based free radicals and proteases
=endothelial damage, increasing vascular permeability. killing and degrading microorganisms. Proteases
degrade various constituents of the extracellular matrix.
4. Arachidonic acid metabolism – Arachidonic acid is an unsaturated fatty acid found in the phospholipids
of cell membranes of inflammatory cells.
- Phospholipases cause release of arachidonic acid, initiating a series of reactions which lead to the
production of prostaglandins, leukotrienes, and lipoxins. These substances (‘eicosanoids’) have effects on
both inflammation and hemostasis; their synthesis is increased at inflammatory sites. - Arachidonic acid metabolism is the target of several commonly used anti-inflammatory agents. I have
included a diagram to illustrate this below. (image with this)
5. Platelet-Activating Factor – this phospholid-derived mediator is generated from the cell membranes of a
variety of cell types (neutrophils, monocytes, endothelium, platelets, etc.), by the action of
phospholipase A. It causes platelet aggregation and activation, vasodilation and increased vascular
permeability, as well as eliciting most of the other features of inflammation.
6. Cytokines – the polypeptide products of activated lymphocytes and macrophages, as well as other cell
types, they modulate the functions of other cells; this group includes colony-stimulating factors, growth
factors, interleukins, and chemokines (which stimulate leucocyte adhesion and chemotaxis). They are
produced during inflammatory and immune responses. Two cytokines are of particular importance:
Interleukin 1 (IL-1) and Tumour Necrosis Factor (TNF)
- produced by activated macrophages
- secretion is stimulated by a variety of inflammatory mediators and injurious stimuli
- induce endothelial activation
- activate tissue fibroblasts
- induce systemic acute-phase responses (fever, lethargy, etc.)
Modifying the inflammatory response with anti-inflammatory agents
- where the inflammatory response is undesirable or excessive. Inflammatory swelling of the spinal cord which
follows intervertebral disc protrusion – this swelling can exacerbate the cord injury and worsen the prognosis.
The identification of these can lead to drugs used to suppress these signs
Corticosteroids or -Glucocorticoids,
- produced naturally by the adrenal cortex and play a role in the stress adaptation response.
- Glucocorticoids suppress or inhibit the inflammatory response. They block the conversion of cell membrane
phospholipids to arachidonic acid.
- diminish vasodilation and decrease permeability, reducing the exudation of both fluid and cells.
- stabilize the lysosomal membranes of inflammatory cells, reducing the release of enzymes and vasoactive
amines. Corticosteroids may similarly suppress virtually all components of the immune response.
- They act by suppressing the response to the injurious agent, and not by treating the cause itself. They must
therefore be used with caution if the inflammatory process has an infectious cause.
NSAIDs (non-steroidal anti-inflammatory drugs)
- Such as aspirin (acetyl salicylic acid), ibuprofen and naproxin. They act by inhibiting the conversion of
arachidonic acid to prostaglandins, and have both anti-inflammatory and analgesic activity.
- Often the first choice for the treatment of chronic inflammatory diseases or mild to moderate pain.
Signs of Acute Inflammation
Local signs: of acute inflammation, redness, heat, swelling and pain.
- heat really only applies to inflammation at the body surface. When the vessels are dilated and more warm
blood moves into the area, then the inflamed area feels warm relative to the surrounding skin.
- A response to injury – it is a component of our “defense” system - Direct stimulation of nerve endings; an injury will thus cause pain and initiate an inflammatory response.
Inflammatory response itself also leads to pain, and the mediators of inflammation are responsible for this
- Polypeptides of low molecular weight, such as bradykinin, histamine and serotonin have a role in signaling
- Increase in tissue tension which occurs due to the swelling of inflammation will also lead to pain
Systemic Signs/ Effects of Inflammation
Systemic (that is, affecting the body generally) signs and symptoms which suggest inflammation include fever,
malaise (“feeling rotten”), changes in the peripheral white blood cell count, and changes in plasma proteins;
collectively these effects are termed the acute phase reaction.
Signs vs Symptoms
Signs: any objective evidence of disease, detectable by a variety of means.
- can become noticed historically (eg.appetite has decreased), signs which become apparent on physical
examination (eg., lymph nodes are enlarged), and signs which are detected through further evaluation with a
variety of procedures (evaluation of blood, fluid or urine samples, radiographs, electrocardiogram ).
Symptoms: on the other hand, refer to any evidence of disease, or changes which the patient can perceive –
such as a pain in the lower abdomen, pain when urinating, and a headache.
Fever: An elevation of body core temperature is referred to as fever.
- Fever-inducing agents (termed pyrogens) can be either endogenous (generated by the body) or exogenous
(factors released by invading organisms, such as bacteria).
Endogenous pyrogens: in acute inflammation include the interleukins (IL-1 and IL-6), and TNF.
- These enter the blood circulation from the site of inflammation and travel to the brain, act at specific loci in
the brainstem(hypothalamus) via prostaglandin synthesis, to cause a “resetting” of the body temperature
- acute inflammation can induce a local heat (due to the increased flow of warm blood into normally cooler
areas at the body surface), but it can also induce the systemic response of fever.
Fever and Hypothermia
The metabolic rate (and thus cell energy and oxygen requirements) increases with fever. Neuronal dysfunction
and delirium will occur at temperatures over 42.2°C (108°F). Death will occur at body temperatures of around
43.3°C (110° F).
Is fever beneficial? fever is a beneficial response which helps the body combat infections, by inhibiting the
growth of some micro–organisms . Fever may be of some help in viral infections, by stimulating interferon
Hypothermia: a lower than normal body core temperature. As the metabolic rate decreases, energy and
oxygen requirements of the cells also decrease. Temps of 21.1 - 23.8°C (70 - 75°F) can be tolerated for short
periods, but if prolonged, coma and death result.
Changes in the peripheral white blood cell count
What cell types are seen in greatest numbers in acute inflammation?
Neutrophils are the most important inflammatory cell type in acute inflammation. They arrive at the site of
inflammation via the bloodstream. Where do these cells come from?
- Normally neutrophils are found in the blood; these “normal” values have been established in humans and other
animal species. If there is increased movement of neutrophils from the bloodstream into the tissues at a site of
inflammation, this will be reflected by changes in the traffic of these cells from the bone marrow reserve into
Leukocytosis : an increased white blood cell count, and a count of the relative numbers of the different white
blood cell types in the blood may show a neutrophilia (increased numbers of neutrophils)
- Immature forms may be seen in the blood – this change is referred to as a “left shift”.
- Left shift indicates that there is a heavy demand for neutrophils, and gives some idea about the extent of the
inflammation. The release of leukocytes from the bone marrow is mediated by the cytokines TNF and IL1
There is an exception to this – in acute viral inflammations, there is often a decreased number of neutrophils
in the blood (neutropenia), and increased numbers of lymphocytes (lymphocytosis); overall, the white blood
cell count is generally decreased (leukopenia) in most viral infections.
Serial evaluations: blood samples can aid in evaluation of the course of the disease and its response to
treatment – this is the ‘practical’ application of this type of information.
Changes in plasma protein levels
Acute inflammation often causes increases in the levels of certain plasma proteins, termed “acute phase
reactants”. These include C-reactive protein, fibrinogen, haptoglobin, and alpha 1-antitrypsin.
- the significance is that increased levels of these substances in the plasma can be detected (via an increased
erythrocyte sedimentation rate), which is a nonspecific indication of the presence of inflammation.
The Course of Acute Inflammation
What are the possible outcomes of acute inflammation?
Think about experiences which you might have had with inflammation, and list at least two outcomes in terms of “what
could happen next”. (If you are “stuck”, think of the example of a sliver in your finger. Once the sliver happens, what are the
Resolution– when acute inflammation is uncomplicated and the swelling and cellular debris are removed by macrophage
activity and lymphatic flow. The tissue returns to normal, and no evidence of the process remains.
2) Repair Because of tissue damage, will be needed before the tissue can return to function. This may involve replacement of
cells by regeneration and/or scar formation. - In some cases, the bacteria which are carried into the tissue cause an exaggerated influx of neutrophils into the area,
leading to liquefactive necrosiss of the tissue.
- The resulting liquefied mass consisting of necrotic tissue, dead organisms and neutrophils is called pus, and the process
of its formation is termed suppurative(or ‘purulent’, not‘pussy’!) inflammation.
- An abscess may form when an area of suppurative inflammation becomes “walled off” by fibrous tissue, as is shown in
the diagram found on the previous page.
The significance of abscess formation
Once an abscess has formed, what happens to it?
1. What might happen to an abscess once it has formed?
2. When might an abscess cause problems?
- The “typical” presentation is that of a tomcat with a large, fluctuant swelling, which can occur just about anywhere,
depending on the extent of the battle. The large canine teeth are ideal to “inoculate” the tissues with bacteria
- Area is often red and warm, and the cat may resent having it touched (pain); if a limb is affected, lameness may be
apparent. Systemic signs (fever/ loss of appetite) (What might you expect to see if a blood sample was examined?)
- Abscesses may go on to rupture and drain pus and heal on their own.
- Small abscesses may resolve without rupture, through removal of the debris by macrophages. If the abscess ruptures but
does not drain adequately, the abscess may reform, or remain as chronic inflammation.
- The worst scenario would be that the bacteria would escape the site, causing local spread of infection (cellulitis) and/or
the systemic spread of infection (septicemia) (see below).
- a possible outcome of acute inflammation (in the instance of inflammation caused by a biologic agent) is that it will not
be effective in destroying the causative agent, and the infectious agent spreads or disseminates.
Septicemia refers to the spread of bacteria and their toxins via the bloodstream (“blood poisoning”). If bacteria are
sufficiently virulent and numerous, and if effective antibiotic therapy is not available, death can result.
Bacteria can also travel in the bloodstream (termed bacteremia) and colonize distant sites, leading to abscess development in
other organs. The valves of the heart are particularly predisposed to this type of colonization.
- If acute inflammation cannot be resolved over a short period of time, it progresses to chronic inflammation. Chronic
inflammation is characterized by a preponderance of mononuclear cell types (as opposed to the neutrophils of acute
inflammation), and also differs from acute inflammation as an immune response has had time to develop.
Tuberculosis or “consumption” is a disease of enormous historical significance. Since the beginning of this century, improved
sanitation and methods of treatment have led to a decline in the prevalence of tuberculosis in most developed countries.
- Evolution of drug-resistant strains of Mycobacterium tuberculosis, tuberculosis has begun to re-emerge as a serious
disease in large urban centers.
- Patients: Systemic signs are often chronic, and include fever, weight loss and fatigue. Local signs include coughing and
hemoptysis (coughing up of blood). These signs are the result of chronic inflammation and necrosis of lung tissue.
Chronic inflammation continued inflammatory response in combination with an immune response against a persistent
injurious agent. Most commonly, these are infectious agents, such as bacteria, fungi, or viruses. However, chemicals or foreign
material, as well as a continued immunologic response can also induce chronic inflammation.
- Acute inflammation can lead to resolution. However, if the inflammation cannot be resolved, because the injurious agent
persists, or healing is interfered with, then chronic inflammation develops.
Chronic inflammation is typically characterized by: some degree of immune response, indicated by the presence of mononuclear (lymphocytes)
infiltration and accumulation of macrophages, which mediate phagocytosis
healing of tissue through the development of granulation tissue, characterized by tissue fibrosis and angiogenesis
(formation of new blood vessels).
ongoing tissue injury and necrosis
- Fibrosis: occurs as a result of attempted repair of affected tissues, and is a common feature of many chronic inflammatory
diseases. This fibrosis can cause problems in itself if it impairs organ or tissue function.
- - The ultimate “goal” of chronic inflammation is to control and eventually eliminate the causal agent from the body.
Whether or not this is successful depends on the extent of the immunologic response– the degree of activation and killing
by T cells, antibody formation by plasma cells and its interaction with the agent, and activation of macrophages by
lymphokines (produced by T cells).
Granulomatous inflammation s generally considered a specific type of chronic inflammation. distinctive pattern of
chronic inflammation characterized by aggregates of activated macrophages that assume an epithelioid
- Granulomas may also develop in response to relatively inert foreign bodies (e.g., suture or splinter),
forming so-called foreign body granulomas.
- granuloma formation does not always lead to eradication of the causal agent, which is frequently
resistant to killing or degradation, and granulomatous inflammation with subsequent fibrosis may even
be the major cause of organ dysfunction in some diseases, such as tuberculosis.
Granulomatous inflammation is characterized by: formation of granulomas
Epithelioid cells : are activated macrophages which have a large amount of foamy pale cytoplasm. The pale foamy cytoplasm
is due to the presence of extensive rough endoplasmic reticulum, which has a secretory function. Such macrophages have an
increased ability to secrete lysozyme and other enzymes, but are not as efficient at phagocytosis.
Why does granulomatous inflammation develop?
Granulomatous inflammation develops when phagocytosis and destruction of a causal agent by macrophages is impaired. This
can occur under several circumstances:
the causal agent is phagocytosed, but survives and persists within the macrophages
phagocytosis of a causal agent is impaired
- An active T cell – mediated immune response must occur. The effector T cells produce lymphocytes which cause the
macrophages to remain in the area (by inhibiting their migration), forming granulomas.
- The classic example of granulomatous inflammation is tuberculosis, in which mycobacteria (Mycobacterium tuberculosis)
survive inside macrophages. Macrophages accumulate in the area, forming the tubercles (granulomas) which characterize the
Differential diagnoses for granulomatous inflammation would include:
1 Atypical bacterium, such as:
A. Mycobacteria spp. (the pathogens involved in tuberculosis and leprosy)
B. Treponema pallidum (the cause of human syphilis)
C. Brucella spp. (the cause of Brucellosis)
2 Fungal pathogens within tissues (such as pulmonary Blastomycosis in dogs, humans)
Parasites within tissues (such as the various lungworms that infest animals and humans)
Inert foreign bodies (such as embedded plant material) Some immune-mediated diseases (such as Crohn’s disease)
Some of these causes may also cause non-granulomatous chronic inflammation
- is still a problem in some tropical areas of the world. Patients who have strong T cell responsiveness against the leprosy
bacillus can localize the infection, and develop granulomas.
- If T cell responsiveness is poor, the bacillus will multiply in macrophages, which accumulate diffusely in the tissue. This
form of the disease is characterized by nodular skin thickening and extensive tissue destruction, with disfiguring
lesions of the fingers and face. Necrotic affected areas of tissue may slough. The bacilli can also spread via the
What happens in affected tissue?
Granulomas are initially microscopic in size, but gradually enlarge with time.
- Functional tissue around the granuloma is lost by necrosis, and replaced by scar tissue. A central area of caseous
necrosis(due to a T cell-mediated Type IV hypersensitivity reaction) is common in granulomas caused by micro-
- Adjacent granulomas may fuse to form large masses, which may be difficult to differentiate from neoplastic (cancerous)
Foreign Body Granulomas
- develop in response to foreign materials (such as sutures, breast implants)
- Foreign body granulomas develop when inert and non-antigenic foreign material enters a tissue, and is too large to be
phagocytosed by a single macrophage.
- Numbers of macrophages congregate around the foreign material and remove it by nonimmune phagocytosis.
- Foreign body giant cells can form in foreign body granulomas. These have numerous nuclei scattered throughout the cell, as
opposed to the Langhans type giant cell with its nuclei at the periphery.
- Ingrown hair or a carbuncle, this is granulomatous inflammation!
- Hairs and surface skin cells are largely made up of keratin, protein that contains numerous sulphur bonds.
- The immune system does not recognize such proteins as “self-proteins”, possibly because keratin is secreted outwardly from
the body, and is “immunologically privileged”
- if large quantities of keratin are injected/embedded within tissues that are routinely monitored by the immune system, then
they induce a foreign body reaction that most typically results in a local granulomatous response “furunculosis reaction”
What about other types of chronic inflammation?
- Presence of epithelioid cells is the defining characteristic of granulomatous inflammation, we can consider any chronic
inflammation not characterized by epithelioid cells as “non-granulomatous” – somewhat of a definition by exclusion.
Non-granulomatous chronic inflammation is characterized by the presence of sensitized lymphocytes, plasma cells and
macrophages(in varying proportions) scattered throughout the affected tissue, along with areas of necrosis and fibrosis.
What causes non-granulomatous chronic inflammation?
Classified into five groups:
Chronic viral infections– cells persistently infected with viruses can evoke a B cell response and a T cell cytotoxic response,
leading to necrosis of the affected cells. The tissue reaction is thus characterized by the presence of lymphocytes and plasma
cells, necrosis, and repair as indicated by fibrosis. (eg., chronic viral hepatitis)
Other chronic infections– certain micro-organisms survive in macrophages once phagocytosed, but evoke an ineffective T cell
response. Large numbers of “foamy” macrophages accumulate diffusely in the tissue, without forming granulomas - these
often contain large numbers of organisms in their cytoplasm.
Chronic autoimmune diseases– there is a similar response to that described above, but with the reaction directed against a
“self” antigen. (eg., rheumatoid arthritis, chronic ulcerative colitis) Allergic conditions and parasitic infections– Large numbers of eosinophils as well as mononuclear cells can accumulate in
tissues affected by repeated or chronic acute hypersensitivity reactions (eg., recurrent Type I hypersensitivity reactions such as
bronchial asthma), and are also associated with various metazoal parasites (eg., nematodes, trematodes).
Chronic toxic diseases– chronic alcohol consumption can cause necrosis of cells of the liver and pancreas; the resulting
alteration of these cells may causes them to become antigenic, leading to an immune response. The chronic inflammation in
these cases is dominated by necrosis and fibrosis; mononuclear cell infiltration may be mild (eg., chronic alcoholic liver
Mixed Acute and Chronic Inflammation
Terms such as chronic active, recurring acute, subacute and chronic suppurative inflammation are often used in pathology, to
describe inflammation which has characteristics of both acute and chronic inflammation.
Chronic suppurative inflammation
- When the body is unable to clear a strong pyogenic (pus-producing) stimulus. This pattern of disease appears as an area
in which there is necrosis and pus formation (suppuration), as well as fibrosis and infiltration of mononuclear cells
(which would include?). Fibrosis may become a prominent feature, with thick fibrous walls delineating areas of
suppurative inflammation and necrosis.
- Initial injection of bacteria into the subcutaneous tissues results in local suppurated inflammation (cellulitis) that can
become quite exuberant, forming large pockets of pus.
- If this infection persists, then the body attempts to prevent the spread of infection by walling the damaged tissue off
with granulation tissue (a mixture of fibrous connective tissue and new capillaries) – the result is an abscess.
- Abscesses are the most typical result of pyogenic bacterial infection that lasts longer than a week. They can occur in any
organ, and appear usually as roughly round cyst-like structures with a thick white fibrous wall and a central cavity
filled with large quantities of pus, necrotic debris, and sometimes fibrin.
- infection of bone with pyogenic bacteria. The bacteria which cause osteomyelitis may arrive by two main routes:
- Bacteria may be carried to the bone by the bloodstream (in septicaemia), termed hematogenous osteomyelitis. The
organisms that cause hematogenous osteomyelitis may enter the bloodstream through a variety of sites, including the
skin or subcutaneous tissues (such as through wounds), gastrointestinal tract (with infectious enteritis or colitis), or
umbilicus (in neonates with umbilical infections).
In growing children and animals, the epiphyseal cartilage (termed the growth plate, as it is the site of ongoing bone
growth) has a particularly abundant blood supply that predisposes this site to bacterial “seeding” with neonatal
septicaemia, the most common cause of osteomyelitis/
Bacteria may develop secondary to extension from a wound or adjacent site of infection. This may occur secondary to
implantation of bacteria into the bone through an open fracture site (bone fractures with contiguous skin wounds) or
orthopaedic surgery incision or by extension from an adjacent cellulitis (an unfortunate complication of perforating
wounds in the hooves of horses and cattle).
- progresses to the chronic phases more often than many other pyogenic bacterial infections as a result of rapid and
severe tissue necrosis. Necrosis of bone occurs particularly rapidly because of the destruction of its blood supply
(both at the site of primary infection, and through formation of subperiosteal abscesses, which disrupt the periosteal
blood supply), causing ischemia of bone. The necrosis of bone and disruption of blood supply results in the formation
of a Sequestrum (pl. sequestra), a fragment of dead, infected bone that persists despite the attempts of the
inflammatory response to clear it out.
View Fig. 20-7 on p. 774 of your textbook, which shows osteomyelitis with sequestrum formation.
Chronic osteomyelitis is difficult to resolve because of the destruction of local blood supply, which is necessary in order to: deliver leukocytes in numbers large enough to destroy the infection and clear the large bulk of necrotic tissue present
deliver systemic antibiotics to the site of infection
Given the disease process as described, what signs and lesions might you expect in a case of chronic osteomyelitis?
• cardinal signs of inflammation (3 points)
• necrosis of bone (2 points)
• systemic inflammatory response (3 points)
See the end of the unit for answers.
Anemia of chronic inflammation
In addition to fever, weight loss, changes in plasma proteins, and leukocytosis, a mild to moderate anemiamay also be a
systemic sign of chronic inflammation.
- anemia of chronic inflammation, also seen with other types of chronic disease, is typically non- regenerative(ie., there is
little evidence of production of new red blood cells). This type of anemia is caused by reduced transport of stored
iron into the plasma, so that hemoglobinization is inadequate and anemia results.
Why is chronic suppurative inflammation often poorly responsive to antibiotic therapy?
When large amounts of pus are formed in chronic inflammation, the causal infectious agents are isolated in an area to which
there is no blood supply, and may not be “accessible” to host defence mechanisms or to antimicrobic drugs (i.e., antibiotics).
The infectious agent may continue to slowly replicate in this site. For this reason, surgical “debulking” of the area may be
important in promoting healing.
Sometimes, chronic inflammation may lead to the deposition of an insoluble fibrillary protein called amyloid in the tissue.
Read the section titled “Amyloidosis” on pages 153-158 of your textbook.
Amyloidosis: a group of diseases characterized by the deposition of similar appearing, insoluble protein (amyloid) in the
interstitium of tissues.
Amyloid consists of “beta-pleated” fibrillar protein; this structural organization is consistent, and the defining
characteristic of what is termed “amyloid”. Microscopically (with H&E stains), amyloid appears as an amorphous
eosinophilic (pink-staining) material. Amyloid can be demonstrated more specifically in tissues using a variety of special
Despite the consistent beta-pleated structure, the underlying chemical structure of the amyloid protein varies,
depending on the source of the precursor protein. Fifteen biochemically distinct forms of amyloid have been identified,
but three are most common:
Serum amyloid-associated (AA), non- immunoglobulin protein , which is produced by the liver during inflammatory
processes as part of the acute phase response. This explains the presence of amyloid in association with some
Immunoglobulin light chains (termed AL amyloid ), produced by some plasma cell or B cell tumour.
Aβ (beta) characterizes the cerebral plaque lesions of Alzheimer disease.
Classification of Amyloidosis
Amyloidosis is usually classified by both biochemical type and tissue distribution: 1. Systemic Amyloidosis
involvement of several organ systems (i.e., generalized involvement). primary and secondary types.
a. Primary amyloidosis (most common form), and is of the AL type. It is associated with a cancer called
multiple myeloma, which is a malignant neoplasm of plasma cells (these terms will be discussed in Unit
7); the abnormal plasma cells may secrete only the ‘light chain’ subunit of immunoglobulin and these
light chains have a role in the AL formation. Other patients have a presumed B cell dysfunction, with
production of abnormal proteins.
b. Systemic (reactive) amyloidosis refers to amyloid depositions which occur widely in the body, often in
association with chronic inflammatory diseases (eg., tuberculosis, chronic osteomyelitis; also chronic
inflammation associated with autoimmune disease). This form of amyloidosis is thus termed ‘secondary’
or reactive amyloidosis.
2. Localized amyloidosisrefers to localized amyloid depositions, within a single tissue or organ.
a. An association has been found between Alzheimer disease and localized deposition of amyloid plaques in
the brain. Further inf