MECHANISM OF INFLAMMATION

Faisal Baloch
BSN
Medicare College Multan

LECTURE - - - - - - > Sources

1. Robbins Pathology
2. Porth Pathophysiology
3. Inam Danish Pathology
 INFLAMMATION
Inflammation is a response of vascularized tissues to infections and tissue
damage that brings cells and molecules of host defense from the circulation
to the sites where they are needed to eliminate the offending agents.

• Inflammation is a response intended to eliminate the initial

cause of cell injury, remove the damaged tissue, and generate
new tissue.
• It accomplishes this by destroying, enzymatically
digesting, walling off, or otherwise neutralizing the harmful
agents such as toxins, foreign agents, or infectious organisms.
TYPES of INFLAMMATION
• 1.Acute inflammation : The initial, rapid response to infections and
tissue damage is called acute inflammation
• 2.Chronic iinflammation: When the initial response fails to clear the
stimulus, the reaction progresses to a protracted type of inflammation
known as chronic inflammation
CAUSES OF INFLAMMATION

1. Infectious agents like bacteria, viruses, fungi, parasites, and microbial toxins
are among the most common cause of inflammation

2. Tissue necrosis elicits inflammation regardless the cause of cell death like
ischemia, trauma, physical and chemical injury

3. Foreign bodies (splinters, dirt, sutures) may elicit inflammation by

themselves or because they ccause traumatic tissue injury or carry microbes

4. Immune reactions (also called hypersensitivity) are reactions in which the

normally protective immune system damages the individual’s own tissues
STEPS OF INFLAMMATORY RESPONSE
5 Rs of inflammatory response are

(1) Recognition of the injurious agent

(2) Recruitment of leukocytes

(3) Removal of the agent

(4) Regulation (control) of the response

(5) Resolution (repair)

PURPOSE OF INFLAMMATION
1. Eliminate the initial cause of cell injury: Inflammation helps to remove
pathogens, toxins, or irritants.

2. Clear out damaged cells and tissues: It removes dead cells and cellular
debris from the site of injury.

3. Initiate tissue repair: Inflammation triggers the healing process and

regeneration of tissues.

4. Contain the spread of infection: It localizes the infection to prevent it from

spreading to other parts of the body.

5. Enhance immune response: Inflammation activates and recruits immune

cells to the site of injury or infection for a more effective defense.
 STAGES OF INFECTIOUS DISEASE
(1) The incubation period, which is the time between the acquisition of
the organism (or toxin) and the beginning of symptoms (this time varies
from hours to days to weeks depending on the organism).

(2) The prodrome period, during which nonspecific symptoms such as

fever, malaise, and loss of appetite occur.

(3) The specific-disease period, during which the overt characteristics

signs and symptoms of the disease occur.

(4) The recovery period, also known as the convalescence period,

CARDINAL SIGNS OF INFLAMMATION
SYSTEMIC MANIFESTATIONS OF INFLAMMATION

• Fever and lethargy Rigors and Chills

• Acute-phase proteins Malaise

• Lymphadenitis Anorexia

• Eosinophilia Somnolence

• Lymphocytosis Increased heart rate

• Neutrophilia Sepsis
 ACUTE INFLAMMATION
"The rapid, short-lived tissue response to injury or infection"

Acute inflammation has three major components:

(1) Dilation of small vessels, leading to an increase in blood flow,

(2) Increased permeability of the microvasculature, enabling plasma proteins and

leukocytes to leave the circulation

(3) Emigration of the leukocytes from the microcirculation, their accumulation in

the focus of injury, and their activation to eliminate the offending agents
 VASCULAR PHASES
The vascular reactions of acute inflammation consists of changes in diameter of
blood vessels, changes in flow of blood and the permeability of vessels.

The escape of fluid, proteins, and blood cells from the vascular system into
interstitial tissues or body cavities is known as exudation.

An exudate is an extravascular fluid that has a high protein concentration

and contains cellular debris

A transudate is a fluid with low protein content, little or no cellular material,

and low specific gravity. It is an ultrafiltrate of blood plasma that is produced as
a result of osmotic or hydrostatic imbalance across vessels with normal
vascular permeability
 SEQUENCE OF EVENTS
Transient vasoconstriction to stop loss of blood in small blood vessels

Vasodilation induced by mediators like histamine and NO, which leads to

erythema and warmth.

Increased permeability of the microvasculature, with the outpouring of a

protein rich fluid (exudate) into the extravascular spaces.

The loss of fluid and increased vessel diameter lead to slower blood
flow, increased viscosity of the blood, resulting in stasis of blood flow
Increased concentration of blood constituents, stagnation of flow,
and clotting of blood at the site of injury.

The loss of plasma proteins reduces the intracapillary osmotic

pressure and increases the osmotic pressure of the interstitial fluid.

Fluid move into the tissues and produce the swelling (edema), pain and
impaired function
 INCREASED VASCULAR PERMEABILITY
It involves two major mechanism..

1. Retraction of endothelial cells resulting in opening of interendothelial spaces

is the most common mechanism of vascular leakage. It is elicited by histamine,
bradykinin, leukotrienes and other chemical mediators. It occurs rapidly after
exposure to the mediator (within 15 to 30 minutes)

2. Endothelial injury , resulting in endothelial cell necrosis and detachment.

Direct damage to the endothelium is encountered in severe injuries, for example,
in burns, or is induced by the actions of microbes and microbial toxins that target
endothelial cells. Neutrophils that adhere to the endothelium during inflammation
may also injure the endothelial cells and thus amplify the reaction
 VASCULAR RESPONSE PATTERNS
The first pattern is an immediate transient response, which occurs with minor
injury. It develops rapidly after injury and is usually reversible and of short
duration (15 to 30 minutes). Typically, this type of leakage affects venules 20
to 60 µm in diameter, leaving capillaries

The second pattern is an immediate sustained response, which occurs with more
serious types of injury and continues for several days. It affects arterioles,
capillaries, and venules and is generally due to direct damage of the
endothelium. Neutrophils that adhere to the endothelium may also injure
endothelial cells.
The third pattern is a delayed hemodynamic response, in which the increased
permeability occurs in the venules and capillarie. A delayed response often
accompanies injuries due to radiation, such as sunburn. The mechanism of the
leakage is unknown, but it may result from the direct effect of the injurious
agents, leading to delayed endothelial cell damage.
 CELLULAR PHASES
The cellular stage of acute inflammation is marked by changes in the
endothelial cells lining the vasculature and movement of phagocytic
leukocytes into the area of injury or infection

The sequence of events in the cellular response to inflammation includes

the following process involving leukocytes
1. Margination and adhesion to the endothelium
2. Transmigration across the endothelium
3. Chemotaxis
4. Activation and phagocytosis
 MARGINATION AND ROLLING
During this process, leukocytes localize to the endothelium, slowing their
migration and beginning to accumulate along the blood vessel. This
accumulation is called margination.

Rolling refers to the initial interaction of leukocytes (white blood cells) with
the endothelial cells lining blood vessels, where the leukocytes roll along the
vessel wall before firmly adhering to it.
ADHESION
Cytokines trigger endothelial cells to express adhesion molecules like selectins,
which bind to leukocytes. This binding slows their movement, causing a rolling
motion along the endothelium. Eventually, leukocytes adhere firmly to
intercellular adhesion molecules (ICAMs) on the endothelial surface.
 TRANSMIGRATION
The adhesion causes the endothelial cells to separate allowing the leukocy
to extend pseudopodia and transmigrate through the vessel wall and then
under the influence of chemotactic factors, migrate into the tissue spaces
CHEMOTAXIS
Chemotaxis is the directed migration of cells, such as leukocytes, guided by
gradients of chemoattractants like chemokines. After exiting capillaries,
leukocytes follow these gradients composed of various substances like
bacterial debris and complement fragments, ensuring their movement
towards sites of infection or injury. This process involves both immune and
non-immune cells secreting chemoattractants to facilitate leukocyte
trafficking.
 LEUKOCYTE ACTIVATION AND PHAGOCYTOSIS
During the final stage of the cellular response, monocytes and neutrophils and tissue
macrophages are activated to engulf and degrade the bacteria and cellular debris in a
process called phagocytosis.
Phagocytosis involves three distinct steps:
(1) Recognition and adherence
(2) Engulfment
(3) Intracellular killing.
 INFLAMMATORY MEDIATORS
Although inflammation is precipitated by infection and injury,
its signs and symptoms are produced by chemical mediators.

Mediators can originate either from the plasma or from cells.

The plasma-derived mediators, which are synthesized in the liver, include the
coagulation factors and the complement proteins. These mediators are present
in the plasma in a precursor form that must be activated by a series of
proteolytic processes to acquire their biologic properties.

Cell-derived mediators are normally sequestered in intracellular granules that

need to be secreted (e.g., histamine from mast cells) or are newly synthesized
(e.g., cytokines) in response to a stimulus.
Cyclooxygenase Lipoxygenase Pathways
 MORPHOLOGIC PATTERNS of
ACUTE INFLAMMATION
The local manifestations can range from swelling and the formation of exudates
to abscess formation or ulceration.
1. Serous Inflammation
Serous exudates are watery fluids low in protein content that result
from plasma entering the inflammatory site.
Serous inflammation is marked by the exudation of cell fluid into spaces
created by injury to surface epithelia or into body cavities lined by the
peritoneum, pleura, or pericardium. Accumulation of fluid in these
cavities is called an effusion.
2. Fibrinous Inflammation.
Fibrinous exudates contain large amounts of fibrinogen and form a thick
and sticky meshwork, much like thefibers of a blood clot.
A fibrinous exudate develops when the vascular leaks are large or there
is a local procoagulant stimulus. With a large increase in vascular
permeability, higher-molecular weight proteins such as fibrinogen pass
out of the blood, and fibrin is formed and deposited in the extracellular
space. A fibrinous exudate is characteristic of inflammation in the lining
of body cavities, such as the meninges, pericardium and pleura.
3. Purulent Inflammation is characterized by the production of pus,
an exudate consisting of neutrophils, the liquefied debris of necrotic
cells, and edema fluid.
The most frequent cause of purulent (also called suppurative)
inflammation is infection with bacteria that cause liquefactive tissue
necrosis, such as staphylococci; these pathogens are referred to as
pyogenic (pus-producing) bacteria.
A common example of an acute suppurative inflammation
is acute aappendicitis
 ABSCESS FORMATION
An abscess is a localized area of inflammation containing a
purulent exudate that may be surrounded by a neutrophil.
Abscesses are localized collections of pus caused by suppuration
buried in a tissue, an organ, or a confined space. They are
produced by seeding of pyogenic bacteria into a tissue layer.
Fibroblasts may eventually enter the area and wall off the
abscess. Because antimicrobial agents cannot penetrate the
abscess wall, surgical incision and drainage may be required to
effect a cure..
4. Ulceration
An ulceration refers to a site of inflammation where an
epithelial surface (e.g., skin or gastrointestinal epithelium)
has become necrotic and eroded, often with associated
subepithelial inflammation. Ulceration may occur as the result of
traumatic injury to the epithelial surface (e.g., peptic ulcer) or because
of vascular compromise (e.g., foot ulcers associated with diabetes).
It is most commonly encountered in (1) the mucosa of the mouth,
stomach, intestines, or genitourinary tract, and (2) the skin and
subcutaneous tissue of the lower extremities in older persons who
have circulatory disturbances that predispose to extensive ischemic
necrosis
Hemorrhagic exudates
It occur when there is severe tissue injury that damages blood
vessels or when there is significant leakage of red cells from
the capillaries.

Membranous or pseudomembranous exudates

It develop on mucous membrane surfaare composed
composed of necrotic cells enmeshed in a fibropurulent
exudate
OUTCOMES OF ACUTE INFLAMMATION
 CHRONIC INFLAMMATION
Chronic inflammation is a response of prolonged duration (weeks or months)
in which inflammation, tissue injury and attempts at repair coexist, in varying
combinations.
Chronic inflammation is characterized by the following morphological patterns
• Infiltration with mononuclear cells, which include macrophages lymphocytes,
and plasma cells.
• Tissue destruction, induced by the persistent offending agents or by the
inflammatory cells
• Attempts at healing by connective tissue replacement of damaged tissue,
accomplished by angiogenesis (proliferation of small blood vessels) and, in
particular, fibrosis
 CAUSES
1. Foreign bodies (such as talc, silica, asbestos, and surgical suture
materials).

2. Viruses

3. Bacteria (e.g., the tubercle bacillus and the treponeme of syphilis).

4. Fungi.

5. Larger parasites of moderate to low virulence.

6. Injured tissue (such as that surrounding a healing fracture).

Nonspecific Chronic Inflammation

Nonspecific chronic inflammation involves a diffuse accumulation of

macrophages and lymphocytes at the site of injury.

Ongoing chemotaxis causes macrophages to infiltrate the

inflamed site, where they accumulate owing to prolonged
survival and immobilization.

These mechanisms lead to fibroblast proliferation, with subsequent scar

formation that in many cases replaces the normal connective tissue or the
functional parenchymal tissues of the involved structures.
For example, scar tissue resulting from chronic inflammation of the bowel
causes narrowing of the bowel lumen.
Granulomatous Inflammation
A granulomatous lesion is a distinctive form of chronic inflammation. A
granuloma typically is a small, 1- to 2-mm lesion in which there is a massing of
macrophages surrounded by lymphocytes. These modified macrophages
resemble epithelial cells and sometimes are called epithelioid cells.
Granulomatous inflammation isassociated with foreign bodies such as
splinters, sutures, silica and asbestos and with microorganisms that cause
tuberculosis, syphilis, sarcoidosis, deep fungal infection and brucellosis.
The epithelioid cells in granulomatous inflammation may clump in a mass or
coalesce, forming a multi nucleated giant cell that attempts to surround the
foreign agent. A dense membrane of connective tissue eventually
encapsulates the lesion and isolates it. These cells are often referred to as
foreign body
giant cells.
 TISSUE REPAIR
Tissue repair is a response to tissue injury and represents an attempt to
maintain normal body structure and function.

It can take the form of regeneration in which the injured cells are replaced
with cells of the same type, sometimes leaving no residual trace of
previous injury
Or
It can take in the form of replacement by connective tissue, which leaves a
permanent scar
Repair of damaged tissues occurs by two types of reactions :
1. Regeneration by proliferation of residual (uninjured) cells and maturation of
tissue stem cells,
2.The deposition of connective tissue to form a scar
 TISSUE REGENERATION
Tissue regeneration involves replacement of the injured tissues with cells of the
same type, leaving little or no evidence of the previous injury

Body organs and tissues are composed of two types of structures:

parenchymal and stromal.

The parenchymal tissues contain the functioning cells of an organ or

body part (e.g., hepatocytes, renal tubular cells)

The stromal tissues consist of the supporting connective tissues, blood

vessels, ECM, and nerve fibers
Body cells are divided into three types according to their ability to
undergo regeneration:
1. Labile cells
2. Stable cells
3. Permanent cells

Labile cells are those that continue to divide and replicate

throughout life, replacing cells that are continually being destroyed.
They include the surface epithelial cells of the skin, oral cavity, vagina,
and cervix; the columnar epithelium of the gastrointestinal tract,
uterus, and fallopian tubes; the transitional epithelium of the urinary
tract; and bone marrow cells.
Stable cells are those that normally stop dividing when growth
ceases. However, these cells are capable of undergoing regeneration
when confronted with an appropriate stimulus and are thus capable
of reconstituting the tissue of origin. This category includes the
parenchymal cells of the liver and kidney, smooth muscle cells, and
vascular endothelial cells.

Permanent or fixed cells cannot undergo mitotic division. The fixed

cells include nerve cells, skeletal muscle cells, and cardiac muscle
cells. These cells do not normally regenerate; once destroyed, they
are replaced with fibrous scar tissue that lacks the functional
characteristics of the destroyed tissues.
 SCAR FORMATION
Connective tissue deposition is called scar formation.

The steps in scar formation are

A) Hemostatic plug and inflammation
B) Proliferation of epithelial cells; formation of granulation tissue by vessel
growth and proliferating fibroblasts.
C) Remodeling to produce the fibrous scar

If the injured tissues are incapable of complete restitution, or if the supporting

structures of the tissue are severely demaged, repair occurs by the laying down
of connective (fibrous) tissue, a process that may result in formation of a scar.
The term fibrosis is most often used to describe the extensive
deposition of collagen that occurs in the lungs, liver, kidney and
other organs as a consequence of chronic inflammation or in the
myocardium after extensive ischemic necrosis (infarction).

If fibrosis develops in a tissue space occupied by an

inflammatory exudate, it is called organization (as in organizing
pneumonia affecting the lung).
 WOUND HEALING
Wound healing involves the restoration of the integrity of
injured tissue is generally divided into three phases:

(1) The inflammatory phase

(2) The proliferative phase

(3) The wound contraction and remodeling phase

 PRIMARY SECONDARY HEALING
Healing of skin wounds can be classified into

1. Healing by first intention (primary union), referring to epithelial

regeneration with minimal scarring, as in well apposed surgical
incisions. (A sutured surgical incision)

2. Healing by second intention (secondary union),

referring to larger wounds that heal by a combination of
regeneration and scarring as in larger wounds (e.g., burns and large surface
wounds)
INFLAMMATORY PHASE
PROLIFERATIVE PHASE
REMODELING PHASE
 FACTORS AFFECTING
WOUND HEALING
1. Malnutrition
2. Impaired blood flow and oxygen delivery
3. Impaired inflammatory and immune responses
4. Infection
5. Wound separation
6. Foreign bodies
7. Aging
8. Specific disorders include diabetes mellitus, peripheral
artery disease, venous insufficiency, and nutritional
disorders.