Inflammation

DR Rufai Yunusa
Pathology Department
 Introduction
• Inflammation is the stereotyped response of living vascularized tissues to injury

• A complex tissue reaction consisting of response of blood vessels and leukocytes.

• The vascular and cellular events are mediated by soluble factors derived from cells and
plasma proteins.

• It is essentially a protective response that ensures the survival of the organism.

• Inflammation may be acute or chronic: depending of the stimulus and effectiveness of the
response.

• Serves to eliminate necrotic tissue and foreign invaders, terminated when offending agents
are removed. It is closely associated with tissue repair following injury.

• Inflammation can be harmful and are associated with certain disease conditions.
 Cardinal Signs of Localized inflammation

• Rubor Redness
• Calor Heat (warmer than other
body parts)
• Tumor Swelling
• Dolor Pain (Tenderness)

• And in the past, a 5th one was added Functio

laesea (Loss of function)
• Acute inflammation is the response of living vascularized tissues to injury
usually of short duration and usually characterized predominantly by a
neutrophilic cellular infiltrates and serves to deliver leukocytes and plasma
protein to sites of infection or tissue injury.

• It is of rapid onset and short duration.

• It has 3 components:

1) Vasodilatation-alteration in vessel caliber leading to increased blood flow.

2) Increased vascular permeability- structural changes in the vasculature
permitting exudation of plasma protein and leukocytes.
3) Leukocytes Emigration - to the site of injury.
 Causes Acute of inflammation

[Link] agents e.g heat, cold, radiations,

mechanical trauma
2. Chemical agents e.g cyanide, acids, alkali
3. Infections e.g bacterial, viral, fungal and
parasitic
4. Immunological agents e.g cell-mediated and
antigen-antibody reactions
5. Foreign bodies e.g dirt, sutures, splinters
5
• Acute inflammation is centered around 2 events:

1) VASCULAR EVENTS
a) Vasodilatation-alteration in vessel caliber leading to increased
blood flow.

b) Increased vascular permeability- structural changes in the

vasculature permitting exudation of plasma protein and leukocytes.

2) CELLULAR EVENTS
a) Leukocyte emigration(Leukocyte extravasations)
b) Phagocytosis.
 VASCULAR EVENTS OF ACUTE INFLAMMATION
Vasodilatation and Increased vascular permeability
• Blood vessel undergo changes to increase the movement of plasma
proteins and cells out of circulation to the site of injury.

• This escape of fluid, protein and cells from the vascular

compartment into the interstitium is referred to as exudation.

• Exudate is an inflammatory derived extracellular fluid that has high

protein concentration, cellular debris and hence high specific gravity.

• In contrast, Transudate is an ultra filtrate of blood plasma and has

low protein concentration, low or no cellular debris and low specific
gravity.
Changes in vascular flow & calibre (Vascular
Events)

Stage 1
Transient vasoconstriction of arterioles
Vasodilatation: 1st arterioles, then opening of new
capillary beds leading to increased blood flow. This
causes heat and redness. Induced by mediators notably
histamine and nitric oxide (NO)
Stage 2.
This is followed by increased permeability of the
microvasculature with outpouring of protein rich fluid
into the extravascular tissue.
Dr Anunobi
Changes in vascular flow & calibre
Stage 3
Concentration of rbc’s in small vessels and increased
viscosity of blood will lead to vascular congestion and
slowing of circulation referred to as Stasis
Accumulation of blood leucocytes along vascular
endothelium. Endothelial cells are activated by
mediators produced at sites of infection leading to
increased expression of adhesion molecules,
adherence of leucocytes to the endothelium and
migration into the interstitial tissue.

Dr Anunobi
 Increased vascular permeability
• Loss of protein from plasma
– Decreased intravascular OP & Increased interstitial
OP
– Marked outflow of fluid into the interstitium
(Oedema)
– Production of this protein-rich fluid – exudate – is
the hallmark of acute inflammation

Dr Anunobi
 Increased vascular permeability
Occurs in distinct phases:
• Immediate transient response – Within 30 minutes,
mediated mainly by histamine and leukotrienes

• Delayed response - about 2 to 8 hours, mediated by

kinins, complement products, and other factors

• Prolonged response - direct endothelial injury, for

example, after burns.

Dr Anunobi
Proposed mechanisms of Vascular Leakage
1. Contraction of endothelial cells
2. Direct Endothelial Injury
3. Leukocyte-mediated Endothelial Injury
4. Increased Transcytosis

Dr Anunobi
 CELLULAR EVENTS IN ACUTE INFLAMMATION

Leukocyte Adhesion to the Endothelium

• Margination- implies the peripheral displacement of WBC along the endothelial surface due to
stasis and hemodynamic changes.

• Rolling- Subsequently, leukocytes adhere transiently to the endothelium, detach and bind again,
thus rolling on the vessel wall. The cells finally come to rest at some point where they adhere firmly
to the endothelial surface.

• Adhesion- The attachment of leukocytes to endothelial cells is mediated by complementary

adhesion molecules on the two cell types. Expression of adhesion molecules are induced by
cytokines are secreted by sentinel cells in tissues in response to microbes and other injurious
agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present
.
• The two major families of molecules involved in leukocyte rolling and adhesion are: Selectins and
Intergrins.
 Cellular Events
• Aim is to deliver leucocytes to site of injury
(Extravasation)
• Activate leucocytes which
– Kill microbes
– Clear necrotic debris & foreign bodies
– Cause tissue damage

Dr Anunobi
 Cellular events
• The histologic feature of inflammation is the
infiltration of leucocytes.
• The sequence of events of leucocyte
extravation is as follows:

Dr Anunobi
 Cellular Events
Emigration
• Margination, Rolling,
Adhesion
• Transmigration
(Diapedesis)
• Migration in interstitium
towards chemotactic
stimulus
• All these processes are
mediated by adhesion
molecules

Dr Anunobi
Dr Anunobi
Dr Anunobi
Selectins: Selectins are involve in Rolling. They are
receptors expressed on cell surface. There are three
types of selectins:
• L-selectin, expressed on leukocytes.
• E-selectin), on endothelium
• P-selectin, on endothelium and leukocytes.

Ligands: for selectins are sialylated oligosaccharides.

• The expression of selectins and their ligands is

regulated by cytokines produced in response to
infection and injury.
Integrins
• Adhesion is mediated by a family of leukocyte
surface proteins called integrins:
VLA-4 β1 integrin: ligand VCAM-1, on endothelial
surface.
LFA-1 β2 integrins : ligand ICAM-1on endothelial
surface.
• TNF and IL-1 released at site of infection or injury
induce endothelial expression of ligands for
integrins on leukocyte surfaces.
Rolling, Adhesion, Emigration
• 3) Leukocyte Emigration: Occurs through a process of migration of the
leukocytes through the endothelium called Transmigration or Diapedesis.

• Adherent leukocytes migrate through interendothelial spaces toward the

chemical concentration gradient to the site of injury or infection
(Chemotaxis).

• Adhesion molecules in interendothelial space such as PECAM 1 aid in

leukocyte extravasation.

• After traversing the endothelium, leukocytes pierce the basement

membrane, probably by secreting collagenases, and enter the
extravascular tissue.
• Chemotaxis : which is defined as locomotion along a chemical
gradient. Both exogenous and endogenous substances can act as
chemoattractants.

• Bacterial products: LPS, Proteoglycans including peptides that

possess an N-formylmethionine terminal amino acid and some
lipids.

• Chemical mediators:
(1) Cytokines,e.g, IL-8.
(2) Components of the complement system, particularly C5a
(3) Arachidonic acid (AA) metabolites e.g LTB4.
• The nature of the leukocyte infiltrate varies with the age of the
inflammatory response and the type of stimulus.

• Neutrophils predominate in the inflammatory infiltrate during

the first 6 to 24 hours and are replaced by macrophages in 24 to
48 hours.

• However, others cells may dominate in other acute

inflammatory responses
– Lymphocytes: esp in Viral infections
– Eosinophils: Parasitic and Hypersensitivity
reaction
4)Phagocytosis: Process of engulfment of solid particulate matter.
(Cell eating). The cells involved in phagocytosis are called
Phagocytes.
• Phagocytosis involves three sequential steps :

(1) Recognition and attachment of the particle to be ingested by the

leukocyte.

(2) Engulfment, with subsequent formation of a phagocytic vacuole.

(3) Killing or Degradation of the ingested material.

 CHEMICAL MEDIATORS OF INFLAMMATION

• General properties of chemical mediators

a. These mediators can be produced Locally, by the CELLS and are called CELL- DERIVED.
Derived from inactive precursors present in plasma which are referred to as PLASMA -
DERIVED .

The cell derived mediators are preformed mediators where as the plasma derived are the
ones which are synthesized de-novo.

b. They can be produced only in response to agents that stimulate inflammation

c. They can stimulate the release of another mediator.

d. They have short lifespan: as they are degraded by enzymatic action very rapidly.

e. They can act on wide variety of cells and may have similar action on different targets or
different actions on similar targets.
CELL DERIVED MEDIATORS-Preformed(stored)

Vasoactive Amines

HISTAMINE: -In mast

cells, basophils &
Platelets.
Vasodilatation and
increase vascular
permeability.

SEROTONIN-in platelets.
Increase vascular
permeability.
 Role of the inflammatory response
• Drainage of fluid exudate into the Iymphatics allows
particulate and soluble antigens to reach the local Iymph
nodes where they may stimulate the immune response.

• Enables cells of the inflammatory response get to the

desired site

• Increased heat at the site of infection activates enzymes

used in the response.

• Prepare grounds for wound healing

What is the outcome of Acute inflammation?

• Resolution
• Healing with scarring (fibrosis)
• Ulceration
• Abscess formation
• Fistula formation
• Sinus formation
• Progression to chronic inflammation
 Chronic Inflammation
– DEFINITION
– AETIOLOGY
– CHARACTERISTICS

Dr Anunobi
 DEFINITION
Inflammation of prolonged duration in which
– active inflammation
– tissue destruction and
– attempts at repair are going on
simultaneously.
• Usually follows acute inflammation
• May also start ab initio as an insidious, low-
grade, smouldering reaction.

Dr Anunobi
 AETIOLOGY
• Persistent infections by certain “tough”
microorganisms
• Prolonged exposure to potentially toxic
agents
• Autoimmunity

Dr Anunobi
 Characteristics
• Infiltration with mononuclear cells
• Tissue destruction
• Attempts at healing
– Angiogenesis
– Fibrosis

Dr Anunobi
 Cells of Chronic Inflammation
• Lymphocytes
• Plasma cells
• Monocytes
• Macrophages

Dr Anunobi
 Granulomatous inflammation
Characterised by:
• Presence of granulomas
– Granulomas are aggregates of epitheliod cells
– Epitheliod cells are transformed macrophages
– Two types- foreign body &immune
• +/- giant cells
– Fusion of epitheliod cells to form a large mass of
cytoplasm and many nuclei (20+)

Dr Anunobi
 definitions
• Edema: accumulation of excess fluid within the
extravascular compartment and interstitial tissue
• Effusion : excess fluid in the cavities of the body
eg pleura
• Transudate: edema fluid with low protein
content (specific gravity less than 1.015).
• Exudate : edema fluid with high protein content (
s g greater than 1.015), associated with
inflammation and contains inflammatory cells,
 Differences between transudate and
exudate
• Transudate is a filtrate of the blood plasma without
changes in the endothelial permeability
• Exudate : Oedema associated with increased vascular
permeability
• Inflammation: associated with exudate, but not associated
with transudate
• Glucose content: same as in plasma for transudate but low
in exudate (<60mg/dl)
• Specific gravity: <1.015 in transudate, but high in exudate
(>1.015)
• pH: >7.3 in transudate, < 7.3 in exudate
• LDH: low in transudate, high in exudate
• Cells: few cells, mainly mesothelial cells and
few debris in transudate, many
cells(inflammatory and parenchymal) in
exudate
• Examples : oedema in CCF is a transudate,
while pus is an eg of exudate
 Systemic effects of inflammation
• Fever
• Leukocytosis
• Production of acute phase reactants

Dr Anunobi
THANK YOU FOR LISTENING

Dr Anunobi