Overview of

Inflammation
Felix E. Menkiti
Department of Anatomic Pathology and Forensic Medicine.
Faculty of Basic Clinical Sciences,
NAU, Nnewi Campus
 OBJECTIVES
▪ To define inflammation and its causes/features
▪ To describe the role of inflammation
▪ To understand the concept: Understand the chain, progression, or
sequence of vascular and cellular events in the histologic evolution
of acute inflammation
▪ To understand the roles of various “chemical mediators” of acute
inflammation
▪ To describe the possible outcomes/fates of acute inflammation
▪ To point out the complications of inflammation
▪ To describe the morphologic patterns of acute inflammation
▪ To understand the causes, morphologic patterns, cells, etc of chronic
and granulomatous inflammation
 Overview of inflammation
Inflammation is the response of living vascularized
tissues to infections and damaged tissues, bringing
cells and molecules of host defense from the
circulation to the sites where they are needed, in
order to eliminate the offending agents.

It is therefore primarily a protective response

essential for survival
➢Rids of cause and consequences of injury
➢May become complicated to become harmful
 Inflammation
• Inflammation is a protective host response
intended to eliminate the initial cause of cell injury
as well as the necrotic cells and tissues resulting
from the original insult

• The reaction of vascularized living tissue to

local injury.
• Inflammation serves to destroy, dilute or isolate the
injurious agent (microbes, toxins) and eliminate the
necrotic cells and tissues.
– Inflammation is part of a broader protective response (innate
immunity )

• It starts a series of events which leads as far as

possible to the healing and reconstitution of the
damaged tissue.

• The components of inflammation are a vascular reaction

and a cellular(leukocytes) response
➢ Activated by mediators that are derived from plasma proteins
and various cells.
➢Include Phagocytes, antibodies, and complement proteins.
• Involves sequence of events
❑Pattern/offending agent recognition by host cells and
recognition molecules
❑Recruitment of Leukocytes and plasma proteins from the
circulation to the site of offence.
❑Activation of leukocytes and proteins, and cooperation to
destroy and eliminate the offending substance.
❑Termination of the process
❑Tissue repair/restoration

➢Remembered as the 5 Rs: Recognition; Recruitment;

Removal; Regulation/control; and Repair/resolution
 Causes of inflammation
• Infections (bacterial, viral, fungal, parasitic) and
microbial toxins
• Tissue necrosis (dead tissues), regardless of its
cause
• Foreign bodies: viz direct, carry microbes, or
causing trauma
– Exogenous (e.g. splinters, dirt, sutures)
– Endogenous (e.g. urate crystals, cholesterol crystals,
lipids)
• Trauma
• Immune responses: (also called hypersensitivity)
• etc.
Recognition of Microbes and Damaged
Cells
• Cellular receptors
– Expressed by epithelial cells, tissue macrophages and
dendritic cells, leukocytes, and other cell types
– Sense the presence of microbes and damage (PAMP
and DAMP).
– Membranous, cytosolic or endosomal receptors
• Other cellular receptors recognize the Fc tail of
Antibodies and complement proteins
• Circulating proteins (complements, mannose-
binding lectin, collectins) recognize microbes that
have entered the blood.
 Mediators of inflammation.
• Soluble factors that are produced by various cells
or derived from plasma proteins

• They are triggered by and are generated or

activated in response to the inflammatory
stimulus.
➢Triggers: Microbes, necrotic cells, hypoxia

• They elicit inflammation:

➢Initiate and amplify the inflammatory response
➢Determine pattern, severity, and clinical and
pathologic manifestations of the inflammatory
response.
 Termination/control of inflammation
• Inflammation is terminated when the offending agent is
eliminated and the secreted mediators are broken down
or dissipated.

• There are active anti-inflammatory mechanisms that

serve to control the response and prevent it from causing
excessive damage to the host.
Outcomes
• Complete resolution: Elimination of the
noxious stimulus followed by decline of the
reaction and repair of the damaged tissue

• Persistence of injury resulting in chronic

inflammation

• Complication, becoming harmful to the body

Types of Inflammation
• Inflammation is divided into:

Acute inflammation.

Chronic inflammation.
 Acute inflammation
 rapid in onset (seconds or
minutes)
 relatively short duration,
lasting for minutes, several
hours, or a few days
 its main characteristics:
 the exudation of fluid and
plasma proteins (edema)
 the emigration of
leukocytes, predominantly
neutrophils.
 Relatively uniform
Chronic inflammation
 Delayed onset
 is of longer duration
 associated histologically with
the presence of lymphocytes
and macrophages, the
proliferation of blood
vessels, fibrosis, and tissue
necrosis.
 Less uniform.
Notes:
Inflammation may be
1. Local and systemic inflammation.
– Localized to the site of infection or damage with
localized features or systemic manifestations (e.g.,
fever in the setting of bacterial or viral pharyngitis)
– Systemic and causing widespread pathologic
abnormalities e.g. disseminated bacterial
infections (sepsis)
2. Acute or chronic
3. Associated with harmful consequences
What are the cells and molecules that
play important roles in inflammation
• leukocytes
• plasma proteins
• cells of vascular walls
• cells of the surrounding connective tissue
• extracellular matrix (ECM) of the surrounding
connective tissue
Tissues and cells involved in inflammatory response :

The fluid and proteins of plasma, circulating cells, blood vessels and
connective tissue

•The circulating cells: neutrophils, monocytes, eosinophils, lymphocytes,

basophils, and platelets.

• The connective tissue cells are the mast cells, the connective tissue
fibroblasts, resident macrophages and lymphocytes.

•The extracellular matrix, consists of the structural fibrous proteins

(collagen, elastin), adhesive glycoproteins (fibronectin, laminin,
nonfibrillar collagen, tenascin, and others), and proteoglycans
Cells and molecules that play important roles in inflammation
The
connective
tissue cells

The circulating cells:

The
extracellul
ar matrix
Harmful consequences of inflammation
• The inflammatory reaction may become harmful, and
no longer protective in some scenarios, giving rise to
disease conditions:
– Misdirected inflammatory response (e.g., against self tissues
in autoimmune diseases),
– Inadequately controlled/exuberant against or against
normally harmless environmental substances
(hypersensitivity reactions e.g. allergies)

• Diseases with underlying inflammatory response

– Hypersensitivity reactions: Anaphylaxis, allergies,
rheumatoid arthritis, etc
– Metabolic diseases: DM2, atherosclerosis,
– Neoplasms: cancer
– Degenerative diseases e.g. Alzheimer disease, lung fibrosis,
Diseases associated with inflammatory reactions
 SUMMARY
• Inflammation is a protective host response to noxious
stimuli, but may become harmful.
• The process involves vascular and cellular events which
are interwoven
• The activation and control are moderated by cellular
and plasma derived mediators.
• It can be localized or systemic
• Classified as acute or chronic
• The outcome: elimination of the offender, persistence of
the process or complication
QUESTIONS???
 Acute
Inflammation
Felix E. Menkiti
Department of Anatomic Pathology and Forensic Medicine.
Faculty of Basic Clinical Sciences,
NAU, Nnewi Campus
• Characteristics
 Rapid in onset (seconds or minutes)
 Relatively of short duration, lasting for minutes, several hours,
or a few days
 its main characteristics:
 the exudation of fluid and plasma proteins (edema)
 the emigration of leukocytes, predominantly neutrophils.
• Two major components (vascular & cellular with 3 events):
– Microvascular dilation leading to an increase in blood
flow
– Increased permeability of the microvasculature enabling
plasma proteins and leukocytes to leave the circulation
– Leukocytes emigration from the microcirculation, with
their accumulation in the focus of injury, and their
activation to eliminate the offending agent
 In summary
• Acute inflammation is a rapid response to an injurious agent
that serves to deliver mediators of host defense-leukocytes
and plasma proteins-to the site of injury.

• Acute inflammation has three main events:

(1) Hemodynamic changes
(alterations in vascular caliber that lead to an increase in blood flow)
(2) Increased vascular permeability
(structural changes in the microvasculature that permit 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 agent)
Components of acute inflammation
Vascular changes Cellular events

 Haemodynamic changes:  Emigration of the leukocytes

alterations in vessel caliber from the microcirculation
resulting in increased and accumulation in the
blood flow focus of injury
 Principal leukocytes in acute
 Increased vascular inflammation are
permeability: permit neutrophils
plasma proteins to leave (polymorphonuclear
the circulation leukocytes).
Triggers/Causes of Acute Inflammation
– Infections (bacterial, viral, parasitic) and
microbial toxins
– Trauma (blunt and penetrating)
– Physical and chemical agents (thermal injury,
e.g., burns or frostbite; irradiation; some
environmental chemicals)
– Tissue necrosis (from any cause)
– Foreign bodies (splinters, dirt, sutures)
– Immune reactions (also called hypersensitivity
reactions)
Source of chemical mediators in
inflammation
• Phagocytes and other host cells
– Leukocyte
– Endothelium
– Mast cell

• Plasma proteins
Cells and molecules that play important roles in inflammation
Actions of chemical mediators in
inflammation
• Some of mediators act on small blood
vessels
• Promote the efflux of plasma
• Recruitment of circulating leukocytes to the
site where the offending agent is located
 Vascular Changes
Designed to maximize the movement of plasma
proteins and leukocytes out of the circulation and
into the site of infection or injury.

(1) Hemodynamic changes

(alterations in vascular caliber that lead to
an increase in blood flow)

(2) Increased vascular permeability

 Vascular Changes
(1) Hemodynamic changes
(alterations in vascular caliber that lead
to an increase in blood flow)
Phases of changes in Vascular Caliber
and Flow
1. Transient vasoconstriction of arterioles
➢ It disappears within 3-5 seconds in mild injuries
➢ It may last several minutes in more severe injury (burn)

2.Vasodilatation:
➢ It involves the arterioles and then results in opening of new
microvasculature beds in the area thus leading to increasing
blood flow
➢ (early hemodynamic change causing heat and redness).

➢ Increased blood volume lead to increased local hydrostatic

pressure leading to transudation of protein -poor fluid into the
extravascular space.
Phases of changes in Vascular Caliber
and Flow
3. Slowing of the circulation due to increased permeability
of the microvasculature, this leads to outpouring of protein-
rich fluid in the extravascular tissues.
➢ This results in concentration of the red cells in small vessels and
increased viscosity of the blood leading to stasis
4. Persistence of stasis
➢ leads to leukocytes (mainly neutrophils) margination and
emigration through the vascular wall into the interstitial tissue.
 Vascular Changes

(2) Increased vascular permeability

 Increased Vascular Permeability
❑A hallmark of acute inflammation (escape
of a protein-rich fluid).
❑Affects small & medium size venules,
through gaps between endothelial cells
Phases of Increased Vascular Permeability
1. Immediate transient response
➢ lasting for 30 minutes or less,
➢ mediated mainly by the actions of histamine and leukotrienes on
endothelium

2. Immediate sustained response

➢ starting at about 2 hours and lasting for about 8hours,
➢ mediated by kinins, complement products, and other factors

3. Prolonged response
➢ that is most noticeable after direct endothelial injury, for example,
after burns.
❑Normal fluid exchange and microvascular permeability are
critically dependent on an intact endothelium.
❑How then does the endothelium become leaky in
inflammation?
Mechanisms for the increased Vascular
Permeability in inflamation
❑Normal fluid exchange and microvascular
permeability are critically dependent on an
intact endothelium

❑How then does the endothelium become

leaky in inflammation?
 Mechanisms 1:
1. Formation of endothelial gaps in venules:
immediate transient response
- The most common mechanism of vascular
leakage
- Due to cytoskeletal retraction
- Elicited by histamine, bradykinin, leukotrienes,
the neuropeptide substance P, cytokines (IL-1,
TNF) and many other classes of chemical
mediators.
- It occurs rapidly after exposure to the mediator
- It is usually reversible and short-lived (15 to 30
minutes)
- Affects venules 20 to 60 μm in diameter, leaving
capillaries and arterioles unaffected
Mechanisms 2
Direct endothelial injury (necrosis and detachment)
Immediate sustained reactions
➢ Damage to the endothelium by the injurious stimulus e.g. burns,
toxins, chemicals, lytic bacterial infections.
➢ Neutrophils may also injure the endothelial cells.
➢ In most instances, leakage starts immediately after injury and is
sustained at a high level for several hours until the damaged
vessels are thrombosed or repaired.
➢ All levels of the microcirculation are affected:
• venules, capillaries, and arterioles.
Mechanisms 3
Leukocyte-mediated endothelial
injury.
Delayed prolonged leakage.
➢ Leukocytes adhere to endothelium
relatively early in inflammation
➢ The adherent leukocytes may be
activated in the process, releasing
ROS and proteolytic enzymes, which
then cause endothelial injury or
detachment.
➢ Results in increased permeability.
➢ Largely restricted to vascular sites,
such as venules and pulmonary and
glomerular capillaries.
Mechanisms 4
Unclear, likely endothelial damage
Delayed prolonged leakage.
• Relatively common type of increased permeability that
begins after a delay of 2 to 12 hours, lasts for several
hours or even days
• May result from the direct effect of the injurious agent,
leading to delayed endothelial cell damage (perhaps by
apoptosis), or the effect of cytokines causing endothelial
retraction.
• Such leakage is caused by mild to moderate thermal
injury, x-radiation or ultraviolet radiation, sunburn and
certain bacterial toxins
• Involves venules as well as capillaries
Mechanisms 5
Increased transcytosis across the endothelial
cytoplasm
• Involve intracellular channels that may be stimulated by certain
factors, such as vascular endothelial growth factor (VEGF), that
promote vascular leakage.
• Its contribution to the overall vascular permeability is
uncertain
Other mechanisms:

• Leakage from new blood vessels.

Mechanisms lead to increased
vascular permeability

➢ Endothelial cell contraction 15-30

min
➢ Endothelial injury
➢ immediate sustained response 6-24
hours
➢ delayed prolonged leakage 12 hours-
days
➢ Leukocyte-mediated endothelial
injury
➢ Transcytosis (occurs via channels
formed by fusion of intracellular
vesicles)
➢ Leakage from new blood vessels
 Marked outflow of fluid and its
accumulation in the interstitial
tissue:
• The loss of protein from the
plasma reduces the intravascular
osmotic pressure and increases
the osmotic pressure of the
interstitial fluid
• the increased hydrostatic
pressure

The net increase of extravascular

fluid results in edema

Slide 3.3
 SUMMARY
 Vascular Reactions in Acute Inflammation
 Vasodilation is induced by chemical mediators such
as histamine , and is the cause of erythema and stasis
of blood flow.
 Increased vascular permeability is induced by
histamine, kinins and other mediators that produce:
• gaps between endothelial cells,
• by direct or leukocyte-induced endothelial injury
• by increased passage of fluids through the endothelium

▪ increased vascular permeability allows plasma proteins and

leukocytes to enter sites of infection or tissue damage;
▪ fluid leak through blood vessels results in edema
 Acute Inflammation
Cardinal clinical features of acute inflammation
➢Heat/calor
➢Redness/Rubor
➢Swelling/Tumour
➢Pain/Dolor
➢Loss of function/Functio laesa
CELLULAR EVENTS OF
INFLAMMATION
• These leukocytes perform the key function of
eliminating the offending agents
•
• The most important leukocytes in acute
inflammatory reactions are the phagocytes,
namely neutrophils and macrophages.

• The movement of leukocytes from the vessel

lumen to the tissue is a multistep process that is
mediated and controlled by adhesion molecules
and cytokines called chemokines.
The cellular events is composed of two
processes:
• EXUDATION OF LEUCOCYTES
• PHAGOCYTOSIS
 EXUDATION OF LEUCOCYTES
3 Steps

In the lumen:
i. Margination Migration in
ii. rolling Transmigration interstitial tissues
iii. adhesion to across the toward a
endothelium chemotactic
endothelium
( diapedesis) stimulus
(NORMALLY
DOESN'T) (Chemotaxis)
Resident tissue macrophages,mast cells, and
endothelial cells respond to injury by secreting the
cytokines TNF, IL-1, histamine and chemokines
which stimulate selectin and stimulate the cells to
migrate toward the site of injury or infection
 EXUDATION OF LEUCOCYTES
This is a multistep process involving attachment
of circulating leukocytes to endothelial cells and
their migration through the endothelium
(extravasation)
• Changes in the formed elements of blood
• Rolling and adhesion
• Emigration
• Chemotaxis
CHANGES IN THE FORMED ELEMENTS OF
BLOOD
• Vasodilatation and stasis slows blood flow
• Change in normal axial blood flow (central
stream of leucocytes & RBCs and peripheral
cell free layer of plasma) in microcirculation.
1. Margination: neutrophils begin to move
towards the periphery of vessels.
– Margination is the first step of leukocytes action
during acute inflammation.
– Neutrophils come close to vessel wall -
Pavementing
2. ROLLING & ADHESION

• Molecules that bring about rolling & adhesion

• i) Selectins
• ii) Integrins
• iii) Immunoglobulin gene superfamily
adhesion molecule
Overview of adhesion molecules and receptors
 SELECTINS

Expressed on the surface of activated endothelial cells

• P –selectin (preformed and stored in endothelial cells and
platelets from Weibel-Palade bodies) is involved in rolling
➢ Bind to Sialyl-Lewis X glycoprotein and slow the leukocytes

• E –selectin (synthesised by cytokine activated endothelial

cells) cause rolling and adhesion
➢ Bind to Sialyl-Lewis X glycoprotein and slow the leukocytes

• L-selectin (expressed on surface of endothelium and

leukocytes)
➢ responsible for homing of circulating lymphocytes to the
epithelial cells in the lymph nodes
➢ Bind to integrin on leukocytes
INTEGRINS

• Present on the endothelial cell surface

• activated during acute inflammation (in
normal situation they are inactive)
• Bind to ligands on endothelial cells (L-selectin)
• Activated by C5a & LTB4 ( small proteins that
stimulate movement of neutrophils and
induce changes in the blood vessels walls )
• Leads to firm adhesion with vessel wall
IMMUNOGLOBULIN GENE SUPERFAMILY ADHESION
MOLECULE
• Intercellular adhesion molecule-1(ICAM-1) and
Vascular cell adhesion molecule-1(VCAM-1)
➢Allow tighter adhesion and
➢Stabilizes the interaction between leucocytes and
endothelial cells
➢Activated by IL-1 and TNF on venular endothelial cells.

• Platelet endothelial cell adhesion molecule-

1(PECAM-1) or CD31
➢found in the extracellular matrix and on cell surfaces.
➢may also been involved in leucocyte migration from the
endothelial surface
 Transmigration or Diapedesis
• Migration of the leukocytes through the
endothelium is called: Transmigration or
Diapedesis
• Occurs in the postcapillary venules
✓ Monocyte-macrophages
appear in next 24-48hrs
✓ Neutrophils are short
lived (24-48hrs)
✓ Monocyte- macrophages
survive longer
Chemotaxis
• Locomotion oriented along a chemical
gradient (Chemoattractants)
• Neutrophils are attracted by bacterial
products, IL-8, C5a & LTB4
• All these chemotactic agents bind to specific
seven-transmembrane G-protein-coupled
receptors on the surface of leukocytes
Potent chemotactic substance or
chemokines of neutrophils:
1. Leukotriene B4 (LT-B4)
2. Components of complement system (C5a and
C3a )
3. Cytokines (interleukines IL-8)
4. Soluble bacterial product
 PHAGOCYTOSIS
• It is the process of engulfment of solid
particulate material by the cell
• Called as Cell eating

TWO TYPES OF PHAGOCYTIC CELLS

❑Polymorphonuclear neutrophils
(microphages)
❑Circulating monocytes (macrophages)
1. Recognition & Attachment
(opsonization)
• The process of coating a particle, such as a
microbe, to target it for phagocytosis
• Opsonins include:
– antibodies (IgG)
– complement proteins (C3b)
– And others: lectins (mannose-binding lectin (MBL),
collectins, fibronectin, fibrinogen, and C-reactive
protein
• These can coat microbes and are recognized by
receptors on phagocytes (Fc and C3b receptors).
2. Engulfment
• Extension of the cytoplasm (pseudopods) of
phagocytes to flow around the particle to be
engulfed,
• Complete enclosure of the particle within a
vacuole – the phagosome
• Fusion of phagocytic vacuole with a lysosomal
granule, resulting in phagolysosome
• The hydrolytic enzymes of the lysosomes
hydrolyzes the cell membrane of the microbe
 3. Killing & Degradation
A. Intracellular mechanism:
– Oxidative bactericidal mechanism by oxygen free
radicals
• a) MPO- dependent
• b) MPO- independent
– Oxidative bactericidal mechanism by lysosomal
granules
– Non- oxidative bactericidal mechanism
B. EXTRACELLULAR MECHANISM
• Granules
– Degranulation of macrophages and neutrophils
and release of lysosomal enzymes
– Lead to proteolysis
• Immune-mechanism
– Immune mediated lysis of microbes occur by
• Cytolysis, antibody mediated lysis and by cell mediated
cytotoxicity
QUESTION???
• THANK YOU