CHAPTER 3
INFLAMMATION.
Inflammation is a local response (reaction) of living vascularized tissues to endogenous and
exogenous stimuli. Inflammation is fundamentally destined to localize and eliminate the
causative agent and to limit tissue injury.
Thus, inflammation is a protective physiologic response to injury.
Causes:
Causes of inflammation are causes of diseases such as;
• physical agents - mechanical injuries, alterations in temperatures and pressure,
radiation injuries.
• chemical agents- including the ever-increasing lists of drugs and toxins.
• biologic agents (infectious)- bacteria, viruses, fungi, parasites
• immunologic disorders- hypersensitivity reactions, autoimmunity, immunodeficiency
states, etc
• genetic/metabolic disorders- examples: gout, diabetes mellitus, etc
Nomenclature:
The nomenclatures of inflammatory lesions are usually indicated by the suffix 'itis'. Thus,
inflammation of the appendix is called appendicitis, and that of the meninges as meningitis, etc
However, like any rule, it has its exceptions, such as pneumonia, typhoid fever, etc
Classification:
Inflammation is classified crudely based on duration of the lesion and histologic appearances
into acute and chronic inflammation.
ACUTE INFLAMMATION.
Acute inflammation is an immediate and early response to an injurious agent and it is relatively
of short duration, lasting for minutes, several hours or few days.
It is characterized by exudation of fluids and plasma proteins and the emigration of
predominantly neutrophilic leucocytes to the site of injury.
The five cardinal signs of acute inflammation are;
• Redness (rubor), which is due to dilation of small blood vessels within damaged tissue,
as it occurs in cellulitis.
• Heat (Calor), which results from increased blood flow (hyperemia) due to regional
vascular dilation.
• Swelling (tumor) which is due to the accumulation of fluid in the extravascular space,
which, in turn, is due to increased vascular permeability.
• Pain (dolor), which partly results from the stretching & destruction of tissues due to
inflammatory edema and in part from pus under pressure in an abscess cavity. Some
chemicals of acute inflammation, including bradykinins, prostaglandins, and serotonin,
are also known to induce pain.
• Loss of function: The inflamed area is inhibited by pain, while severe swelling may also
physically immobilize the tissue.
Events of acute inflammation:
Acute inflammation is categorized into early vascular and late cellular responses.
1) The Vascular response has the following steps:
• Immediate (momentary) vasoconstriction in seconds due to neurogenic or chemical
stimuli to reduce any blood loss due to injury.
• Vasodilatation of arterioles and venules; resulting in increased blood flow to deliver
immune cells and other mediators to the site of injury.
• After the phase of increased blood flow, there is a slowing of blood flow & stasis due to
increased vascular permeability that is most remarkably seen in the post-capillary
venules. The increased vascular permeability oozes protein-rich fluid into extravascular
tissues. Due to this, the already dilated blood vessels are now packed with red blood
cells, resulting in stasis. The protein-rich fluid, which is now found in the extravascular
space, is called exudate. The presence of the exudates clinically appears as swelling.
Chemical mediators mediate the vascular events of acute inflammation.
2) Cellular response
The cellular response has the following stages:
A. Migration, rolling, pavementing, & adhesion of leukocytes
B. Transmigration of leukocytes
C. Chemotaxis
D. Phagocytosis
Normally blood cells particularly erythrocytes in venules are confined to the central (axial) zone
and plasma assumes the peripheral zone. As a result of increased vascular permeability (See
vascular events above), more and more neutrophils accumulate along the endothelial surfaces
(peripheral zone).
A) Migration, rolling, pavementing, and adhesion of leukocytes.
• Margination is a peripheral positioning of white cells along the endothelial cells.
• Subsequently, rows of leukocytes tumble slowly along the endothelium in a process
known as rolling.
• In time, the endothelium can be virtually lined by white cells. This appearance is called
pavementing
• Thereafter, the binding of leukocytes with endothelial cells is facilitated by cell adhesion
molecules such as selectins, immunoglobulins, integrins, etc. which result in adhesion of
leukocytes with the endothelium.
B). Transmigration of leukocytes
• Leukocytes escape from venules and small veins but only occasionally from capillaries.
The movement of leukocytes by extending pseudopodia through the vascular wall
occurs by a process called diapedesis.
• The most important mechanism of leukocyte emigration is via widening of
interendothelial junctions.
C). Chemotaxis:
• A unidirectional attraction of leukocytes from vascular channels towards the site of
inflammation within the tissue space guided by chemical gradients (including bacteria
and cellular debris) is called chemotaxis.
• The most important chemotactic factors for neutrophils are components of the
complement system (C5a), bacterial and mitochondrial products of arachidonic acid
metabolism such as leukotriene B4 and cytokines (IL-8). All granulocytes, monocytes
and to lesser extent lymphocytes respond to chemotactic stimuli.
• How do leukocytes "see" or "smell" the chemotactic agent? This is because receptors
on cell membrane of the leukocytes react with the chemoattractants resulting in the
activation of phospholipase C that ultimately leads to release of cytosolic calcium ions
and these ions trigger cell movement towards the stimulus.
D) Phagocytosis
• Phagocytosis is the process of engulfment and internalization by specialized cells of
particulate material, which includes invading microorganisms, damaged cells, and tissue
debris.
• These phagocytic cells include polymorphonuclear (granulocytes) leukocytes
(particularly neutrophiles), monocytes and tissue macrophages.
Phagocytosis involves three distinct but interrelated steps.
1) Recognition and attachment of the particle to be ingested by the leukocytes:
Phagocytosis is enhanced if the material to be phagocytosed is coated with certain plasma
proteins called opsonins. These opsonins promote the adhesion between the particulate
material and the phagocyte’s cell membrane. The three major opsonins are: the Fc fragment of
the immunoglobulin, components of the complement system C3b and C3bi, and the
carbohydrate-binding proteins – lectins.
2). Engulfment:
During engulfment, extension of the cytoplasm (pseudopods) flow around the object to be
engulfed, eventually resulting in complete enclosure of the particle within the phagosome
created by the cytoplasmic membrane of the phagocytic cell. As a result of fusion between the
phagosome and lysosome, a phagolysosome is formed, and the engulfed particle is exposed to
the degradative lysosomal enzymes.
3) Killing or degradation
The ultimate step in phagocytosis of bacteria is killing and degradation. There are two forms of
bacterial killing.
I. Oxygen-independent mechanisms: These are cellular processes that do not rely on
reactive oxygen species (ROS) to eliminate pathogens, particularly bacteria. It involves
the use of proteins and enzymes such as; Bactericidal permeability increasing protein
(BPI), a protein in the human innate immune system that is involved in eliminating gram-
negative bacteria, Lysozymes which digest the bacterial debris, Lactoferrin, which binds
to iron and disrupts the bacterial cell membrane. It is probable that bacterial killing by
lysosomal enzymes is inefficient and relatively unimportant compared with the oxygen
dependent mechanisms. The lysosomal enzymes are, however, essential for the
degradation of dead organisms within phagolysosomes.
II. Oxygen-dependent mechanism: involve the production of reactive oxygen species (ROS)
by phagocytic cells to kill pathogens. These ROS, including superoxide radicals, hydrogen
peroxide, and hydroxyl radicals, are highly reactive molecules that damage the
pathogen's cellular components by reacting with molecules in cell membrane or
nucleus.
CHEMICAL MEDIATORS OF INFLAMMATION.
Chemical mediators of inflammation are molecules that signal and regulate the inflammatory
response, initiating and coordinating immune responses.
Inflammation has the following sequence: Cell injury, Chemical mediators, Acute inflammation
(i.e., the vascular & cellular events).
Sources of chemical mediators:
The chemical mediators of inflammation can be derived from plasma or cells.
a) Plasma-derived mediators:
• Complement activation; complement proteins increases vascular permeability
(C3a, C5a), activates chemotaxis (C5a), opsonization (C3b, C3bi)
• Factor XII (Hegman factor) activation; Its activation results in recruitment of four
systems: the kinin, the clotting, the fibrinolytic and the compliment systems.
b) Cell-derived chemical mediators:
Mediator, cells of origin, and functions in italics below.
Histamine; Mast cells, basophiles, Vascular leakage
Serotonin; Platelets, Vascular leakage
Lysosomal enzymes; Neutrophiles, Bacterial & tissue destruction
Prostaglandins: All leukocytes, Vasodilatation, pain, fever
Platelet-activating factor; All leukocytes, Bronchoconstriction and WBC priming
Nitric oxide; Macrophages, Leukocyte activation
Cytokines; Macrophages, Leukocyte activation
Most mediators perform their biological 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 the production of exudates. An
exudate is an edema fluid with high protein concentration, which frequently contains
inflammatory cells/WBC.
A transudate is simply a non-inflammatory edema caused by cardiac, renal, under-nutritional,
& other disorders.
The differences between an exudate and a transudate are;
Exudate transudate
Cause: Acute inflammation non-inflammatory disorders
Appearance; Colored, turbid, hemorrhagic Clear, translucent or pale yellow
Protein content: present/ high No protein
Cells: Abundant WBC, RBC, & Cell debris usually present Only few mesothelial cells
Bacteria: Present Absent.
There are different morphologic types of acute inflammation:
1) Serous inflammation
This is characterized by an outpouring of a thin fluid that is derived from either the blood serum
or the secretion of mesothelial cells lining the peritoneal, pleural, and pericardial cavities.
It resolves without reactions.
2) Fibrinous inflammation
A type of inflammatory response characterized by the deposition of fibrin.
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.
3) Suppurative (Purulent) inflammation
This type of inflammation is characterized by the production of a large amount of pus. Pus is a
thick creamy liquid, yellowish or blood stained in color and composed of; A large number of
living or dead leukocytes (pus cells), Necrotic tissue debris, living and dead bacteria, and Edema
fluid.
There are two types of suppurative inflammation:
• Abscess formation: An abscess is a circumscribed (localized) accumulation of pus in a
living tissue. It is encapsulated by a so-called pyogenic membrane (separates the abscess
from healthy tissue), which consists of layers of fibrin, inflammatory cells, and
granulation tissue.
• Acute diffuse (phlegmonous) inflammation; This is characterized by diffuse spread of
the exudate through tissue spaces. It is caused by virulent bacteria (eg, streptococci)
without either localization or marked pus formation. Example: Cellulitis (in palmar
spaces).
4) Catarrhal inflammation; This is a mild and superficial inflammation of the mucous
membrane. It is commonly seen in the upper respiratory tract following viral infections
where mucous-secreting glands are present in large numbers, eg, Rhinitis.
5) Pseudomembranous inflammation; this is a type of inflammation characterized by the
formation of a false (pseudo) membrane which forms a white or colored layer over the
surface of the inflamed mucosa. It consists of fibrinogen, the necrotic epithelium, the
neutrophilic polymorphs, red blood cells, bacteria and tissue debris.
Pseudomembranous inflammation is exemplified by Dipthetric infection of the pharynx
or larynx and Clostridium difficile infection in the large bowel following certain antibiotic
use.
EFFECTS OF ACUTE INFLAMMATION:
Beneficial effects
• Dilution of toxins: The concentration of chemical and bacterial toxins at the site of
inflammation is reduced by dilution in the exudate and its removal from the site by the
flow of exudates from the venules through the tissue to the lymphatics.
• Protective antibodies: Exudation results in the presence of plasma proteins including
antibodies at the site of inflammation. Thus, antibodies directed against the causative
organisms will react and promote microbial destruction by phagocytosis or complement-
mediated cell lysis.
• Fibrin formation: This prevents bacterial spread and enhances phagocytosis by
leukocytes.
• Plasma mediator systems provisions: The complement, coagulation, fibrinolytic, & kinin
systems are provided to the area of injury by the process of inflammation.
• Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen and
other nutrients to meet the metabolic requirements of the greatly increased number of
cells. It also removes their solute waste products via lymphatic channels.
• Promotion of immunity: Micro-organisms and their toxins are carried by the exudates,
either free or in phagocytes, along the lymphatics to local lymph nodes where they
stimulate an immune response with the generation of antibodies and cellular immune
mechanisms of defense.
Harmful effects
• Tissue destruction Inflammation may result in tissue necrosis.
• Swelling: The swelling caused by inflammation may have serious mechanical effects at
certain locations. Examples include acute epiglottitis with interference in breathing;
Acute meningitis and encephalitis with effects of increased intracranial pressure.
• Inappropriate response: The inflammatory seen in hypersensitivity reactions is
inappropriate (i.e. exaggerated).
COURSE OF ACUTE INFLAMMATION.
Acute inflammation may end up in:
➢ Resolution: i.e. complete restitution of normal structure and function of the tissue, eg,
lobar pneumonia.
➢ Healing by fibrosis (scar formation).
➢ Abscess formation {Surgical law states -Thou shall (you should) drain all abscesses.}
However, if it is left untouched, it may result in;
- Sinus formation - when an abscess cavity makes contact with only one epithelial lining.
- Fistula formation: when an abscess tract connects two epithelial surfaces.
-Or very rarely to septicemia or Pyemia with subsequent metastatic abscess in heart,
kidney, brain etc.
