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Learning Objectives

•

At the end of the lecture you have to know

What is inflammation and its types

What are the major components of
inflammation.

The roles of inflammatory mediatores

Clinical significace of inflammation.

Inflammation

Acute

Chronic

Granulamatous

Define inflammation?

Inflammation is defined as the response of a living
vascularized tissue to harmful agents.

It consists principally of:

vascular changes associated with leukocytes infiltration
and systemic reaction.

Inflammation is fundamental and common
pathologic process seen in many disease states.

What are the types of inflammation???

Acute inflammation:

 Rapid in onset (seconds or minutes).
 Relatively short duration (minutes, hours, or at most a few days).
 Characterized by the exudation of fluid and plasma proteins.
 The emigration of leukocytes, predominantly neutrophils

Chronic inflammation

 Is of insidious onset.
 Longer duration.
 Associated histologically with the presence of lymphocytes,

macrophages, plasma cells.

 Proliferation of blood vessels and fibroblasts

In both forms of inflammation:

Tissue necrosis of varying extent occurs.
The vascular and cellular reactions of both acute

and  chronic  inflammation  are  mediated  by
chemical  substances  (chemical  mediators)  that
are derived from plasma proteins or cells.

Such substances, acting singly, in combinations,

or in sequence, amplify the inflammatory
response and influence its evolution.

What are the cardinal signs of
inflammation??

Rubor

Calor

Tumor

Dolor

(functio laesa)

HISTORICAL

HIGHLIGHTS

Acute inflammation

STIMULI

for acute inflammation

• INFECTIOUS
• PHYSICAL
• CHEMICAL

• Tissue Necrosis
• Foreign Bodies (FBs)
• Immune “responses”, or “complexes”

Exudation:



Is the escape of fluid, proteins, and blood

cells from the vascular system into the

interstitial tissue.

 An exudate is an extravascular fluid that

has a high protein concentration and a
specific gravity above

1.020

It involves significant alteration in the

normal permeability of small blood vessels

in the area of injury.

Transudate:

Is a fluid with low protein content (most of

which is albumin)

A specific gravity of less than

1.012

It is essentially an ultrafiltrate of blood plasma

that results from osmotic or hydrostatic
imbalance across the vessel wall without an
increase in vascular permeability.

What are the major components of acute
inflammation?

A. Vasodilation associated with increased

blood flow.

B. Increased vascular permeability

associated with decreased blood flow.

C. Emigration and activation of leukocytes

and phagocytosis.

Vascular Changes

• Changes in Vascular Flow and

Caliber

• Increased Vascular

Permeability

and increased blood flow :

Vasodilation



This is, sometimes, preceded by a transient

constriction of arterioles, lasting a few seconds.

 Vasodilation first involves the arterioles, which

leads to an increase in blood flow; this in turn leads
to opening of new capillary beds in the area with
subsequent dilation of capillaries & venules.

This process allows more blood to flow into the

area, a process known as “active hyperemia”
(hyper- = increased; -emia = blood). These changes
explain the clinically noted heat and redness.

Vasodilation is induced by the

action of several mediators (such
as histamine) on vascular smooth
muscles.

Autonomic nerve impulses may

also play a role in relaxation of
arteriolar smooth muscle leading
to their dilation.

B. Increased Vascular Permeability and decreased
blood flow:

Increased vascular permeability leads to the

escape of exudates into the extravascular tissue.

This is driven by the increased hydrostatic

pressure  owing  to  increased  blood  flow
through  the  dilated  vessels  and  is
perpetuated  through  the  loss  of  proteins
from  the  plasma  that  reduces  the
intravascular

osmotic

pressure

and

increases the osmotic pressure of the
interstitial fluid.

hat are the mechanisms of increased vascular

permeability??

due to

venules

Formation of endothelial gaps in

is elicited by

endothelial cells contraction

bradykinin

histamine,

several mediators e.g.

leukotrienes

and

Binding of these mediators to receptors on
endothelial cells leads to stimulation of
contractile proteins (such as myosin). The
result is contraction of the endothelial cells
and separation of intercellular junctions that
eventuate in intercellular gaps formation.

retraction

Junctional

caused by chemical mediators such as
TNF and IL-1;

these induce structural reorganization of
the cytoskeleton of the cells

3. Direct endothelial cell injury as by burns

or infections

Because of endothelial

damage

and

exposure

the

subendothelial thrombogenic collagen,
this type is frequently associated with
platelets

adhesion

with

subsequent

thrombosis.

4. Leukocyte-dependant injury due to

accumulation  of  leukocytes  and  their
activation  products  (such  as  toxic  oxygen
radicals  and  proteolytic  enzymes)  during
the  inflammatory  response.

These lead to

endothelial cell damage.

phagocytosis

Emigration and activation of leukocytes and

A critical function of inflammation is to :
• Deliver leukocytes to the site of injury
• Activate the leukocytes to defend the host.
Leukocytes:
  offending agents
 Kill bacteria and other microbes.
 Get rid of necrotic tissue and foreign substances.
However, these cells may induce tissue damage and prolong

inflammation.

 The journey of leukocytes from the vessel lumen to the

interstitial tissue is called extravasation.

This can be divided into the following steps:

EXTRAVASATION of PMNs

• MARGINATION

(PMN’s go toward
wall)

• ROLLING

(tumbling

and HEAPING)

• ADHESION
• TRANSMIGRATION

(DIAPEDESIS)

Sequence of events in leukocytes emigration in inflammation:

1. Margination 2. rolling 3. adhesion 4. transmigration and movement

toward injurious agent (stimulus)

Emigration of neutrophils

What is Chemotaxis???

Chemotaxis is defined as locomotion

oriented along a chemical gradient of
chemoattractants.

All granulocytes, monocytes and, to a lesser

extent, lymphocytes respond to
chemoattractants (chemotactic stimuli) with
varying rates of speed.

Both exogenous and endogenous substances can

act as chemoattractants. The former is
exemplified by bacterial products.

• Enumerate the Endogenous chemoattractants

Endogenous chemoattractants, however,
include several chemical mediators:

1. Components of the complement system,

particularly C5a

2. Products of the lipoxygenase pathway,
mainly leukotriene B4 (LTB4)

3. Cytokines (secreted from cells) e.g., IL-8

What are the steps of

phagocytosis?

PHAGOCYTOSIS

RECOGNITION

ENGULFMENT

KILLING
DEGRADATION/DIGESTION)

Phagocytosis involves three distinct but
interrelated steps:

1. Recognition and attachment of the particle
to be ingested by the leukocyte

2. Its engulfment, with subsequent formation
of a phagocytic vacuole

3. Killing and degradation of the ingested
material.

The efficiency of phagocytosis is greatly

enhanced  when  microbes  are  opsonized  by
specific  proteins  (opsonins)  for  which  the
phagocytes  express  high-affinity  receptors.
The major opsonins are

IgG
C3b
Plasma lactin.

………………………………………………………………………
…………………………..

• Microbial killing is accomplished largely by

oxygen-dependent

mechanisms,

which

depends on the production of

reactive oxygen

species

particularly

H2O2..

Oxygen-

independent  degradation  depends  on  the
release  of  granules,  containing  proteolytic
enzymes  such  as  defensins  (antibacterial
peptide  attacking  bacterial  cell  membrane),
proteolytic  enzymes  such  as  elastases,
lysozymes, and cationic proteins

Cells of acute inflammation

Cells

Activity

Phagocytosis Inflammation

Neutrophil

Proteases,
oxidases

Acute

Eosinophil

histamine

Acute,
Chronic

Macrophage

Antigen
processing,
digestion

Late acute,
chronic

CHEMICAL MEDIATORS OF

INFLAMMATION

CHEMICAL MEDIATORS

• From plasma or cells
• Have “triggering” stimuli
• Usually have specific targets
• Can cause a “cascade”
• Are short lived

CLASSIC MEDIATORS

• HISTAMINE
• SEROTONIN
• COMPLEMENT
• KININS
• CLOTTING FACTORS
• Arachidonic acid

metabolites

• NITRIC OXIDE

• PLATELET ACTIVATING

FACTOR (PAF)

• CYTOKINES
• /CHEMOKINES
• LYSOSOME

CONSTITUENTS

• FREE RADICALS
• NEUROPEPTIDES

HISTAMINE

• Mast Cells,

basophils

• POWERFUL

Vasodilator

• Vasoactive

“amine”

• IgE on mast cell

SEROTONIN

• (5HT

ydroxy-

ryptamine

)

• Platelets and

EnteroChromaffin Cells

• Also vasodilatation, but

more indirect

COMPLEMENT SYSTEM

• i.

Vascular phenomena:

C3a, C5a

stimulate histamine release from
mast cells and thereby increase
vascular permeability and cause
vasodilation.

• ii.

Chemoattractants:

for e.g. C5a is

a powerful chemotactic agent for
neutrophils, monocytes,
eosinophils, and basophils.

• iii.

Opsonins:

when fixed to the

bacterial cell wall, C3b acts as an
opsonin and favor phagocytosis by
neutrophils and macrophages.

KININ SYSTEM

• BRADYKININ is KEY component
• ALSO from circulating plasma
• BRADYKININ

has actions similar to those of

histamine.

CLOTTING

FACTORS

• Also from circulating plasma
• Coagulation, i.e., production of fibrin

• triggering recruitment of leukocytes

EICOSANOIDS

(ARACHIDONIC ACID DERIVATIVES)

Part of cell membranes

Prostaglandins

(incl.

Thromboxanes)

Leukotrienes

Lipoxins

(new)

MULTIPLE ACTIONS AT MANY LEVELS

Prostaglandins

(thromboxanes included)

• Pain

•

TxA2 is a potent platelet-aggregating

agent and a vasoconstrictor

• Prostacyclin, has actions opposing that

of TxA2 in that it is a vasodilator, a
potent inhibitor of platelet aggregation

Leukotrienes

Chemotaxis

The principal actions of
lipoxins are to inhibit
neutrophil chemotaxis and

adhesion to endothelium

latelet-

ctivating

actor

(PAF)

• Phospholipid
• From MANY cells
• ACTIVATE PLATELETS,

powerfully

CYTOKINES/CHEMOKINES

• CYTOKINES

are PROTEINS produced by MANY

cells, but usually LYMPHOCYTES and
MACROPHAGES, numerous roles in acute and
chronic inflammation

–TNFα

IL-1

by macrophages

• CHEMOKINES

are small proteins which are

attractants for PMNs

ITRIC

XIDE

• Potent vasodilator

• NO and its derivatives are

microbicidal, and thus NO is
also a mediator of host
defense against infection

LYSOSOMAL CONSTITUENTS

• PRIMARY

• Also called

AZUROPHILIC, or
NON-specific

• Myeloperoxidase
• Lysozyme (Bact.)
• Acid Hydrolases

• SECONDARY

• Also called

SPECIFIC

• Lactoferrin
• Lysozyme
• Alkaline Phosphatase
• Collagenase

FREE RADICALS

• O2

–

(SUPEROXIDE)

•H2O2

(PEROXIDE)

•OH

(HYDROXYL RADICAL)

•

VERY VERY

DESTRUCTIVE

NEUROPEPTIDES

• SUBSTANCE P

which has many

biologic functions, including the
transmission

pain

signals,

regulation of blood pressure, and
increasing vascular permeability

Appendix: acute suppurative inflammation

ulceration and undermining by an

extensive neutrophilic exudate

Upper half of excised appendix.

Lt: fibrino-purulent serosal
exudate

Rt: lumen filled with pus

acute appendicitis: mucosal inflammation and necrosis.

Microscopically, acute appendicitis is marked by mucosal inflammation and necrosis.

Transmural inflammation in acute appendicitis

Neutrophils extend into and through the wall of the appendix in a case of acute appendicitis.
Clinically, the patient often presents with right lower quadrant

abdominal pain. Rebound tenderness is noted on physical examination. An elevated WBC count is
usually present.

Acute pneumonia, microscopic

Acute bronchopneumonia, microscopic

The PMN's seen here are in alveoli, indicative of an acute bronchopneumonia of the lung. The
PMN's form an exudate in the alveoli. This patient had a "productive

“ cough because large

amounts of purulent sputum were produced. The source is seen here.