MODULE 3:INFLAMMATION - Chronic inflammation can eventually cause several

diseases and conditions, including some cancers,

rheumatoid arthritis,
Inflammation, is the body's attempt at self-protection; the aim being to
- atherosclerosis, periodontitis, and hay fever.
remove harmful stimuli, including damaged cells,
- Although scientists know that inflammation plays a key
irritants, or pathogens - and begin the healing process. When something
role in heart disease and several other illnesses, what
harmful or irritating affects a part of our body, there is a biological
drives
response to try to remove it, the signs and symptoms of inflammation,
- inflammation in the first place is still a mystery.
specifically acute inflammation, show that the body is trying to heal
It should be remembered that inflammation is part of the healing process.
itself. Inflammation does not mean infection, even when an infection
Sometimes reducing inflammation is
causes inflammation. Infection is caused by a bacterium,virus or
necessary, but not always.
fungus, while inflammation is the body's response to it.
Fast facts on inflammation
- Inflammation is the body's attempt at self-protection to
Causes
remove harmful stimuli and begin the healing process. 1. Causes of inflammation are apparently causes of diseases such as
● physical agents - mechanical injuries, alteration in
- Inflammation is part of the body's immune response.
temperatures and pressure, radiation injuries.
- The first stage of inflammation is often called irritation,
● chemical agents- including the ever increasing lists of drugs
which then becomes inflammation - the immediate and toxins.
healing process. ● biologic agents (infectious)- bacteria,viruses,fungi, parasites
- Inflammation is followed by suppuration (discharging of ● immunologic disorders- hypersensitivity reactions,
pus). Then there is the granulation stage, the formation autoimmunity, immunodeficiency states etc
in wounds of tiny, rounded masses of tissue during ● genetic/metabolic disorders- examples gout, diabetes mellitus
healing. etc...
- Acute inflammation - starts rapidly (rapid onset) and Nomenclature:
quickly becomes severe. - The nomenclatures of inflammatory lesions are usually indicated by the
- Chronic inflammation - this means long-term suffix 'itis'. Thus, inflammation of the appendix is called
inflammation, which can last for several months and appendicitis and that of meninges as meningitis, etc....
even years. However, like any rule, it has its own exceptions, for example
- Our infections, wounds and any damage to tissue would pneumonia, typhoid fever, etc....
never heal without inflammation - tissue would become
more and more damaged and the body, or any
organism, would eventually perish.
Classification:
- Inflammation is classified crudely based on duration of the lesion and ➢ Swelling (tumor) which is due to accumulation of fluid in the
histologic appearances into acute and chronic inflammation. extravascular space which, in turn, is due to increased vascular
ACUTE INFLAMMATION permeability.
➔ Acute inflammation is an immediate and early response to an injurious ➢ Pain (dolor), which partly results from the stretching &
agent and it is relatively of short duration, lasting for minutes, destruction of tissues due to inflammatory edema and in part
several hours or few days. from pus under pressure in an abscess cavity. Some chemicals
➔ It is characterized by exudation of fluids and plasma proteins and the of acute inflammation, including bradykinins, prostaglandins
emigration of predominantly neutrophilic leukocytes to the site and Serotonin are also known to induce pain.
of injury. ➢ Loss of function (Functio Laesa): The inflamed area is inhibited
➔ Starts rapidly (rapid onset) and quickly becomes severe. Signs and by pain while severe swelling may also physically immobilize
symptoms are only present for a few days, but in some cases the tissue.
may persist for a few weeks. EVENTS OF ACUTE INFLAMMATION
➔ Examples of diseases, conditions, and situations which can result in - Acute inflammation is categorized into an early vascular and a late
acute inflammation include: cellular response.
➔ Acute bronchitis 1) The Vascular response has the following steps:
➔ Infected ingrown toenail ● a) Immediate (momentary) vasoconstriction in seconds due to
➔ Sore throat from a cold or flu neurogenic or chemical stimuli.
➔ A scratch/cut on the skin ● b) Vasodilation of arterioles and venules resulting in increased
➔ Exercise (especially intense training) blood flow.
➔ Acute appendicitis ● c) After the phase of increased blood flow there is a slowing of blood
➔ Acute dermatitis flow & stasis due to increased vascular permeability that is most
➔ Acute tonsillitis remarkably seen in the post-capillary venules. The increased vascular
➔ Acute infective meningitis permeability oozes protein-rich fluid into extravascular tissues.
➔ Acute sinusitis 2) Cellular response, The cellular response has the following stages:
➔ A blow. A. Migration, rolling, pavementing, & adhesion of leukocytes -
FIVE CARDINAL SIGNS Margination is a peripheral positioning of white cells along the
- The five cardinal signs of acute inflammation are: endothelial cells. Subsequently, rows of leukocytes tumble slowly
along the endothelium in a process known as rolling.In time, the
➢ Redness (rubor) which is due to dilation of small blood vessels endothelium can be virtually lined by white cells. This appearance is
within damaged tissue as it occurs in cellulitis. called pavementing Thereafter, the binding of Leukocytes with
➢ Heat (calor) which results from increased blood flow endothelial cells are facilitated by cell adhesion molecules such as
(hyperemia) due to regional vascular dilation selectins,immunoglobulins, integrins, etc which result in adhesion of
leukocytes with the endothelium.
B. Transmigration of leukocytes - Leukocytes escape from venules and phagolysosome is formed and the engulfed particle is exposed to the
small veins but only occasionally from capillaries. The movement of degradative lysosomal enzymes.
leukocytes 3).Killing or degradation - The ultimate step in phagocytosis of bacteria
by extending pseudopodia through the vascular wall occurs by a is killing and Degradation. There are two forms of bacterial killing:
process called diapedesis. The most important mechanism of a) Oxygen-independent mechanism
leukocyte emigration is via widening of inter-endothelial junctions after b) Oxygen-dependent mechanism
endothelial cells contractions. The basement membrane is disrupted CHEMICAL MEDIATORS OF INFLAMMATION
and resealed thereafter immediately. - Chemical mediators account for the events of inflammation. Inflammation
C. Chemotaxis - A unidirectional attraction of leukocytes from vascular has the following sequence: Cell injury 🡪 Chemical mediators 🡪 Acute
channels towards the site of inflammation within the tissue space inflammation (i.e. the vascular & cellular events).
guided by chemical gradients (including bacteria and cellular debris) is - Mediators derived from plasma include complement and complement-
called chemotaxis. The most important chemotactic factors for derived peptides and kinins. The kinins are also important inflammatory
neutrophils are components of the complement system (C5a), bacterial mediators. The most important kinin is bradykinin, which increases
and mitochondrial products of arachidonic acid metabolism such as vascular permeability and vasodilation and, importantly, activates
leukotriene B4 and cytokines (IL-8). All granulocytes, monocytes and phospholipase A2 (PLA2) to liberate arachidonic acid (AA). Bradykinin is
to lesser extent lymphocytes respond to chemotactic stimuli. also a major mediator involved in the pain response.
D. Phagocytosis - Phagocytosis is the process of engulfment and - Other mediators are derived from injured tissue cells or leukocytes
internalization by specialized cells of particulate material, which recruited to the site of inflammation. Mast cells, platelets, and basophils
includes invading microorganisms, damaged cells, and tissue debris. produce the vasoactive amines serotonin and histamine.
These phagocytic cells include polymorphonuclear leukocytes - Histamine causes arteriolar dilation, increased capillary permeability,
(particularly neutrophiles), monocytes and tissue macrophages. contraction of nonvascular smooth muscle, and eosinophil chemotaxis and
Phagocytosis involves three distinct but interrelated steps. Recognition can stimulate nociceptors responsible for the pain response.
and attachment of the particle to be ingested by the leukocytes Sources of mediators:
Phagocytosis is enhanced if the material to be phagocytosed is coated The chemical mediators of inflammation can be derived from plasma or
with certain plasma proteins called opsonins. These opsonins promote cells.
the adhesion between the particulate material and the phagocyte’s cell A) Plasma-derived mediators:
membrane. i) Complement activation
2).Engulfment - During engulfment, extension of the cytoplasm - increases vascular permeability (C3a,C5a)
(pseudopods) flow around the object to be engulfed, eventually - activates chemotaxis (C5a)
resulting in complete enclosure of the particle within the phagosome - opsonization (C3b,C3bi)
created by the cytoplasmic membrane of the phagocytic cell. As a ii) Factor XII (Hegman factor) activation
result of fusion between the phagosome and lysosome, a
 - Its activation results in recruitment of four systems: the kinin,
the clotting, the fibrinolytic and the complement systems.
B) Cell-derived chemical mediators:
- Cell-derived chemical mediators include:
- Most mediators perform their biologic activities by initially binding to
specific receptors on target cells. Once activated and released from
the cells, most of these mediators are short lived. Most mediators have
the potential to cause harmful effects.

MORPHOLOGY OF ACUTE INFLAMMATION

- Characteristically, the acute inflammatory response involves
production of exudates. An exudate is an edema fluid with high ● Serous inflammation
protein concentration, which frequently contains inflammatory - This is characterized by an outpouring of a thin fluid that is
cells. derived from either the blood serum or secretion of mesothelial
- A transudate is simply a non-inflammatory edema caused by cells lining the peritoneal, pleural, and pericardial cavities.
cardiac, renal, undernutrition - It resolves without reactions
● Fibrinous inflammation
- More severe injuries result in greater vascular permeability
that ultimately leads to exudation of larger molecules such as
fibrinogens through the vascular barrier.
- Fibrinous exudate is characteristic of inflammation in serous
body cavities such as the pericardium (butter and bread
appearance) and pleura.
- Course of fibrinous inflammation include:
, & other disorders.
1. Resolution by fibrinolysis
- The differences between an exudate and a transudate are:
2. Scar formation between parietal and visceral
surfaces i.e. the exudates get organized
3. Fibrous strand formation that bridges the
pericardial space.

● Suppurative (Purulent) inflammation

- This type of inflammation is characterized by the production of ○ The fibrinogens in the inflamed tissue coagulate
a large amount of pus. within the necrotic epithelium. And the
- Pus is a thick creamy liquid, yellowish or blood stained in color fibrinogen, the necrotic epithelium, the neutrophil
and composed of: polymorphs, red blood cells, bacteria and tissue
1. A large number of living or dead leukocytes (pus debris form a false (pseudo) membrane which
cells) forms a white or colored layer over the surface of
2. Necrotic tissue debris inflamed mucosa.
3. Living and dead bacteria ○ Pseudomembranous inflammation is exemplified
4. Edema fluid by Diphtheritic infection of the pharynx or larynx
- There are two types of suppurative inflammation: and Clostridium difficile infection in the large
➢ Abscess formation: An abscess is a circumscribed bowel following certain antibiotic use.
accumulation of pus in a living tissue. It is encapsulated EFFECTS OF ACUTE INFLAMMATION
by a so-called pyogenic membrane, which consists of A. Beneficial effects
layers of fibrin, inflammatory cells and granulation ★ Dilution of toxins: The concentration of chemical and bacterial
tissue. toxins at the site of inflammation is reduced by dilution in the
➢ Acute diffuse (phlegmonous) inflammation: This is exudate and its removal from the site by the flow of exudates
characterized by diffuse spread of the exudate through from the venules through the tissue to the lymphatics.
tissue spaces. It is caused by virulent bacteria ★ Protective antibodies: Exudation results in the presence of
(eg.streptococci) without either localization or marked plasma proteins including antibodies at the site of inflammation.
pus formation. Example: Cellulitis (in palmar spaces). Thus, antibodies directed against the causative organisms will
➢ Catarrhal inflammation :This is a mild and superficial react and promote microbial destruction by phagocytosis or
inflammation of the mucous membrane. It is commonly complement-mediated cell lysis.
seen in the upper respiratory tract following viral ★ Fibrin formation: This prevents bacterial spread and enhances
infections where mucous secreting glands are present phagocytosis by leukocytes.
in large numbers, eg. Rhinitis. ★ Plasma mediator systems provisions: The complement,
➢ Pseudomembranous inflammation: coagulation, fibrinolytic, & kinin systems are provided to the
■ The basic elements of area of injury by the process of inflammation.
pseudomembranous inflammation are ★ Cell nutrition: The flow of inflammatory exudates brings with it
extensive confluent necrosis of the glucose, oxygen and other nutrients to meet the metabolic
surface epithelium of an inflamed requirements of the greatly increased number of cells. It also
mucosa and severe acute inflammation removes their solute waste products via lymphatic channels.
of the underlying tissues.
 ★ Promotion of immunity: Micro-organisms and their toxins are - Chronic inflammation can be defined as a prolonged
carried by the exudates, either free or in phagocytes, along the inflammatory process (weeks or months) where an active
lymphatics to local lymph nodes where they stimulate an inflammation, tissue destruction and attempts at repair are
immune response with the generation of antibodies and cellular proceeding simultaneously.
immune mechanisms of defense. - This means long-term inflammation, which can last for several
B. Harmful effects months and even years. It can result from:
★ Tissue destruction: Inflammation may result in tissue necrosis - Failure to eliminate whatever was causing an acute
and the tissue necrosis may, in turn, incite inflammation. inflammation
★ Swelling: The swelling caused by inflammation may have - An autoimmune response to a self antigen - the immune
serious mechanical effects at certain locations. Examples system attacks healthy tissue, mistaking it (them) for harmful
include acute epiglottitis with interference in breathing; Acute pathogens.
meningitis and encephalitis with effects of increased intracranial - A chronic irritant of low intensity that persists.
pressure. - Examples of diseases and conditions with chronic inflammation
★ Inappropriate response: The inflammatory seen in include:
hypersensitivity reactions is inappropriate (i.e.exaggerated). - Asthma
COURSE OF ACUTE INFLAMMATION - Chronic peptic ulcer
Acute inflammation may end up in: - Tuberculosis
● Resolution: i.e. complete restitution of normal structure and - Rheumatoid arthritis
- Chronic periodontitis
function of the tissue, eg. lobar pneumonia.
- Ulcerative colitis and Crohn's disease
● Healing by fibrosis (scar formation).
- Chronic sinusitis
● Abscess formation {Surgical law states -Thou shall (you should) - Chronic active hepatitis
drain all abscesses.} However, if it is left untouched, it may CAUSES OF CHRONIC INFLAMMATION
result in 1. Persistent infections - Certain microorganisms associated with
○ Sinus formation: when an abscess cavity makes contact intracellular infection such as tuberculosis, leprosy, certain fungi etc
with only one epithelial lining. characteristically cause chronic inflammation. These organisms are of
○ Fistula formation: when an abscess tract connects two low toxicity and evoke delayed hypersensitivity reactions.
epithelial surfaces. Or very rarely to septicemia or 2. Prolonged exposure to non degradable but partially toxic
Pyemia with subsequent metastatic abscess in heart, substances. Either endogenous lipid components which result in
kidney, brain etc. atherosclerosis or exogenous substances such as silica, asbestos.

CHRONIC INFLAMMATION 3. Progression from acute inflammation: Acute inflammation almost

always progresses to chronic inflammation following: Persistent
suppuration as a result of uncollapsed abscess cavities, foreign body
materials (dirt, cloth, wool, etc), sequestrum in osteomyelitis, or a
sinus/fistula from chronic abscesses.
4. Autoimmunity - Autoimmune diseases such as rheumatoid arthritis
and systemic lupus erythematosus are chronic inflammations from
the outset.
CELLS OF CHRONIC INFLAMMATION
● Monocytes and Macrophages are the prima Donna (primary
cells) in chronic inflammation. Macrophages arise from the
common precursor cells in the bone marrow, which give rise to
blood monocytes. CLASSIFICATION OF CHRONIC INFLAMMATION
● These cells are then diffusely scattered in various parts of the Nonspecific chronic inflammation:
body, in the liver (Kupffer cells), spleen, lymph nodes (sinus - This involves a diffuse accumulation of macrophages and
histiocytes), lungs (alveolar macrophages), bone marrow, brain lymphocytes at site of injury that is usually productive with new
(microglia), skin (Langerhans cells), etc.... These cells fibrous tissue formations. E.g. Chronic cholecystitis.
constitute the mononuclear- phagocytic system. Specific inflammation (granulomatous inflammation):
● Macrophages are scavenger cells of the body. - Granulomatous inflammation is characterized by the presence
Other cells in chronic inflammation: of granuloma. A granuloma is a microscopic aggregate of
● 1. T-Lymphocytes are primarily involved in cellular immunity epithelioid cells. Epithelioid cell is an activated macrophage,
with lymphokine production, and they are the key regulator and with a modified epithelial cell-like appearance (hence the name
effector cells of the immune system. epithelioid)
● 2. B-lymphocytes and Plasma cells produce antibodies directed There are two types of giant cells:
either against persistent antigen in the inflammatory site or
against altered tissue components. ➢ a. Foreign body-type giant cells which have irregularly
● 3. Mast cells and eosinophils appear predominantly in response scattered nuclei in presence of indigestible materials.
to parasitic infestations & allergic reactions. Though neutrophils ➢ b. Langhans giant cells in which the nuclei are arranged
are hallmarks of acute inflammatory reactions, large numbers peripherally in a horse -shoe pattern which is seen
of neutrophils may be seen in some forms of chronic typically in tuberculosis, sarcoidosis etc... Giant cells are
inflammation, notably chronic osteomyelitis, actinomycosis, & formed by fusion of macrophages perhaps by a
chronic lung diseases induced by smoking and other stimuli. concerted attempt of two or more cells to engulf a single
particle.
Pathogenesis: SYSTEMIC EFFECTS OF INFLAMMATIONS
● Foreign body granuloma a. Fever- Fever is the most important systemic manifestation of
-These granulomas are initiated by inert foreign bodies such inflammation. It is coordinated by the hypothalamus &
as talc, sutures (non-absorbable), fibers, etc... that are large by cytokines (IL -1, IL-6, TNF-α) released from macrophages
enough to preclude phagocytosis by a single macrophage and other cells.
and do not incite an immune response. b. Endocrine & metabolic responses -The liver secrets acute
● Immune granulomas phase proteins such as: C-reactive proteins, Serum Amyloid A,
-Antigen presenting cells (macrophages) engulf a poorly and Complement and coagulation proteins. Glucocorticoids
soluble inciting agent. Then, the macrophage processes (increased) Vasopressin (decreased)
and presents part of the antigen (in association with MHC type2 c. Autonomic responses- Redirection of blood flow from the
molecules) to CD4+T helper 1 cells which become activated. cutaneous to the deep vascular bed. Pulse rate and blood
The activated CD4+ T-cells produce cytokines (IL-2 and pressure (increased) Sweating (decreased)
interferon gamma). d. Behavioral responses -Rigor, chills, anoroxia, somnolence,
-The IL-2 activates other CD4+T helper cells and perpetuates and malaise.
the response while IFN-γ is important in transforming e. Leukocytosis- Common feature of inflammation, especially
macrophages into epithelioid cells and multinucleated giant in bacterial infections. Its usual count is 15,000 to 20,000
cells. The cytokines have been implicated not only in the cells/mm3. Most bacterial infections induce neutrophilia. Some
formation but also in the maintenance of granuloma. viral infections such as infectious mononucleosis, & mumps
-Macrophage inhibitory factor helps to localize activated cause lymphocytosis. Parasitic infestations &
macrophages and epithelioid cells. allergic reactions such as bronchial asthma & hay fever
Major causes of granulomatous inflammation include: induced eosinophilia.
f. Leukopenia- is also a feature of typhoid fever and some
● a) Bacterial: Tuberculosis, Leprosy, Syphilis, Cat parasitic infections.
scratch disease, Yersiniosis g. Weight loss- is thought to be due to the action of IL-1 and
● b) Fungal: Histoplasmosis, Cryptococcosis, TNF-α which increase metabolism in skeletal muscle, adipose
Coccidioidomycosis, Blastomycosis tissue and the liver with resultant negative nitrogen balance.
● c) Helminthic: Schistosomiasis
● d) Protozoal: Leishmaniasis, Toxoplasmosis
● e) Chlamydia: Lymphogranuloma venerum
● f) Inorganic material: Berrylliosis
● g) Idiopathic: Acidosis, Cohn’s disease, Primary biliary
cirrhosis
 increase the risk of stroke and myocardial infarction
(heart attack).
➔ Acetaminophen (paracetamol, Tylenol) can reduce pain
associated with inflammatory conditions, but have no anti-
inflammatory effects. They may be ideal for those wishing to
treat just the pain, while allowing the inflammation to run its
course.

➔ Corticosteroids
● These are a class of steroid hormones naturally produced in
the cortex (outer portion) of the adrenal gland. They are
synthesized in laboratories and added to medications.
PHARMACOLOGICAL MANAGEMENT ● Corticosteroids, such as cortisol are anti-inflammatory; they
- As mentioned, patients (and many health care professionals) prevent phospholipid release, which undermines eosinophil
must remember that inflammation is part of the healing action and a number of other mechanisms involved in
process. Sometimes reducing inflammation is necessary, but inflammation.
not always. ○ Glucocorticoids, which are produced as a reaction to
Anti-inflammatory medications stress, and are also involved in metabolizing fats,
➔ NSAIDs (non-steroidal anti-inflammatory drugs) are taken to proteins and carbohydrates. Synthetic glucocorticoids
alleviate pain caused by inflammation. They counteract the are prescribed for inflammation of the joints (arthritis),
COX (cyclooxygenase) enzyme, which synthesizes temporal arteritis dermatitis, inflammatory bowel
prostaglandins which create inflammation. If prostaglandin disease, systemic lupus, hepatitis, asthma, allergic
synthesis can be blocked, pain is either eliminated or reduced. reactions, and sarcoidosis. Creams and ointments
- Examples of NSAIDs include naproxen, ibuprofen and (topical formulations) may be prescribed for
aspirin. inflammation of the skin, eyes, lungs, bowels and nose.
- People should not use NSAIDs long-term without being ○ Mineralocorticoids, which regulate our salt and water
under the supervision of a doctor, because there is a balance. Medications with mineralocorticoids are used
risk of stomach ulcers, and even severe and life- for the treatment of cerebral salt wasting, and to replace
threatening hemorrhage. NSAIDs may also worsen missing aldosterone (a hormone) for patients with
asthma symptoms and cause kidney damage. NSAID adrenal insufficiency.
medications, with the exception of aspirin, can also
● Corticosteroid side effects are more likely if taken in oral form,
compared to inhalers or injections. The higher the dosage
and/or the longer they are taken for, the greater the risk of side
effects. Side effect severity is also linked to dosage and
duration of treatment. Patients taking oral corticosteroids for
over three months have a considerably greater chance of
experiencing undesirable side effects.
● Inhaled medications, such as those to treat asthma over the
long-term raise the risk of developing oral thrush - rinsing the
mouth out with water after each application can help prevent
oral thrush.
● Gucocorticoids can also induce Cushing's syndrome, while
mineralocorticoids can cause high blood pressure
(hypertension), low blood potassium levels (hypokalemia), high
blood-sodium levels (hypernatremia), connective tissue
weakness and metabolic alkalosis.