Inflammation

Ketevan Gambashidze

MD., Ph.D., D.Sc.

AssociateProfessor

Robbins - Basic Pathology (9th

edition)
pp. 29 - 59

Inflammation

is a defensive reaction, mechanism, by which the body deals with

an injury or insult.

The inflammatory response is designed to inactivate and remove the injurious agent,
remove any damaged tissue resulting from the injury and accomplish repair.

Acute inflammation is the early, almost immediate response of a tissue to

injury
and first line of defense against injury.

Inflammation is the nonspecific reaction of organism and may be evoked by any

injury.

The acute inflammatory response involves the following processes:

Alteration

Emigration of leukocytes
from blood vessels to the

(destroy of
cells, tissues)

area of injury

Changes in
microcirculation

exudation

Proliferation
with

of

connective tissue (healing)

of fluid

Cardinal signs of
inflammation:
Rubor
(redness)

Calor
(increased heat)

Tumor
(swelling)

Dolor
(pain)

Functio laesa
(loss of
function)

Redness-rubor
An acutely inflamed tissue appears red. This is due to dilatation of small blood vessels within the
damaged area.

Heat-calor

Increase in temperature is due to the entry of a large amount of blood at body core
temperature into the normally cooler skin as a result of hyperemia.

Swelling-tumor
Swelling results from edema, the accumulation of fluid in the extra vascular space as a result of
increased hydrodynamic pressure (hyperemia) and increased permeability of capillaries.

Pain-dolor
It results partly from the stretching and distortion of tissues due to inflammatory edema
and, in particular, from pus under pressure in an abscess cavity. Some of the chemical
mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin, are
known to induce pain.

Lossoffunction

Loss of function, a well-known consequence of inflammation, was added by Virchow (1821-1902) to the
list of features drawn up by Celsus. Movement of an inflamed area is consciously and reflexly inhibited by
pain, while severe swelling may physically immobilize the tissues.

The steps involved in e acute inflammatory response are:

1. Initially immediate, temporary and transient vasoconstriction. The direct response
to injury.
2.

Small blood vessels (capillaries) adjacent to the area of tissue damage become

dilated with increased blood flow, then flow along them slows down.
3. Endothelial cells swell and partially retract so that they no longer form a completely
intact internal lining.
4. The vessels become leaky, permitting the passage of water, salts, and some small
proteins from the plasma into the damaged area (exudation). One of the main proteins to
leak out is the small soluble molecule, fibrinogen.
5. Circulating neutrophil polymorphs initially adhere to the swollen endothelial cells
(margination, capture, rolling, adhesion) then actively migrate through the vessel
basement membrane (emigration), passing into the area of tissue damage.
6.Later, small numbers of blood monocytes (macrophages) migrate in a similar way, as do
Lymphocytes.

The principal chemical mediators of inflammation

EC, Endothelial cells.

Tissue injury

Cell-derived inflammatory
mediators

Plasma-derived inflammatory
mediators
Hageman factor

Platelet
s
Mast
cells

Serotoni
n

(XII)

Inflammator
y cells

Arachidoni
c acid
metabolite
s

KallikreinClotting Fibrinolytic Comple

system system
system
ment
system
Platelet
activating
factor (PAF)

Lymphokines & Monokines

Histamin
e

Plasmin

Kinins

Fibrin
degradation
products

Complemen
t
components

Generation of arachidonic acid metabolites and their roles in inflammation.

Note the enzymatic activities whose inhibition through pharmacologic intervention blocks major pathways

(denoted with a red X).

COX-1, COX-2 - Cyclooxygenase 1 and 2; HETE - hydroxyeicosatetraenoic acid; HPETE - hydroperoxyeicosatetraenoic acid.

Sources and effects of

nitric oxide (NO)
in inflammation.

NO synthesized by
endothelial cells (mostly
via endothelial cell [type
III] NO synthase [eNOS])
and by macrophages
(mostly via inducible
[type II] NO synthase
[iNOS]) causes
vasodilation and reduces
platelet and leukocyte
adhesion;

NO produced in
phagocytes is also
cytotoxic to microbes.

Capillaries at

Inflammation

Beneficial effects of the

exudate are:
Dilution of toxins

Fibrin formation

Dilution of toxins, such as those

produced

by

them

be

to

bacteria,
carried

Fibrin formation from fibrinogen may

allows

away

impede the movement of microorganisms,

in

trapping

lymphatics.

them

and

so

facilitating

phagocytosis.

Entry of antibodies
Increased

vascular

permeability

allows

Delivery of nutrients
and O2

antibodies to enter the extravascular space, where

Delivery of nutrients

they may lead either to Iysis of microorganisms,

and oxygen, essential for

through the participation of complement, or to

cells such as neutrophils

their phagocytosis by opsonisation. Antibodies are

which have high metabolic

also important in neutralisation of toxins.

activity.

Stimulation of immune response

The

drainage

Iymphatics

allows

of

exudate

soluble

into

antigens

Drug transport

the
to

The

fluid

therapeutic

carries

drugs

such

reach the Iymph nodes where they may

antibiotics

stimulate the immune response.

bacteria are multiplying.

to

the

with

site

it
as

where

Harmful effects of the

exudate are:
Digestion of normal tissues
Enzymes such as collagenases and proteases may digest normal tissues,
resulting in their destruction.

Swelling
The swelling of the epiglottis in acute epiglottitis in children due to Haemophilus
influenzae infection may obstruct the airway. Inflammatory swelling is especially
serious when it occurs in an enclosed space such as the cranial cavity.

Inappropriate inflammatory response.

Sometimes,
inappropriate,

acute
such

inflammatory
as

those

responses

which

hypersensitivity reactions (e.g. hay fever).

occur

in

appear
type

The principal cells of the acute

Following injury, the

inflammatory response are the

neutrophils migrate out of

neutrophils and macrophages.

the vessels

The movement of neutrophils out of the vessels

and their role in combat can be divided into
discrete steps:

1.
Margination
2. Capture

3. Rolling

4.
Adhesion
5. Emigration

6.
Chemotaxis
7. Phagocytosis
and degranulation

The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium,
pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury.
Different molecules play predominant roles in different steps of this process - selectins in rolling; chemokines (usually
displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm
adhesion; and CD31 (PECAM-1) in transmigration.
ICAM-1 - intercellular adhesion molecule 1; IL-1 - interleukin 1; PECAM-1 - platelet endothelial cell adhesion molecule 1; TNF tumor necrosis factor.

Mechanism of Leukocytes movement

The cells are able to move towards a chemical signal, this specific movement
being termed chemotaxis.
The compounds that have been suggested as chemotactic agents include:
1.
Bacterial products
2.Fragments of the Complement system

C5a

3. Products of arachidonic acid metabolism Prostaglandines and

Leukocyte emigrates toward the site of injury along a chemical gradient.
Leukotriens
1.

Chemotactic agent binds to specific receptors on the leukocyte cell membrane

that activates

G-protein.

2. Active G protein in turn activates Phospholipase C that hydrolysis membrane

phospholipids

and

phosphatidylinositol

biphosphate

(PIP2) turns into inositol

triphosphate (IP3) and diacyl glycerol (DAG).

3.IP3

increases ionized Calcium level within the cytoplasm. The increased cytosolic

calcium triggers the assembly of sytoskeletal contractile elements (actin and myosin)
necessary for movement.

Mechanism of Leukocytes
movement

Formation of
pseudopods

Besides stimulating locomotion, chemotactic factors also induce other

leukocyte responses, generally referred to as Leukocyte activation
[ligand binds leukocyte receptor activation of G-protein activation
of phospholipase C membrane phospholipids hydrolysis PIP2 IP3
and DGA protein kinase C protein phosphorylation, secretory
granule degranulation and secretion, oxidative burst, phospholipase A 2
(arachidonic acid, production of IL and LT-s), increased number and
affinity of adhesion molecules integrins).

Bacteria coated with certain substances are ingested more readily. The
factors that coat bacteria are called opsonins, and the process is termed
opsonisation. This is derived from the Greek word "opson" meaning
"relish" i.e. getting ready for eating.

Two major opsonins:

Ig-G

C3b

immunoglobulin

component of
complement

Receptors on the cell surface of Neutrophils and Macrophages for

recognition of Opsonins
Fc fragment
for Ig-G

Surface receptor
for C3b

Bacterial killing
Mechanisms in Phagolysosome:

Oxygen- dependent

Oxygen-independent
Lysozyme - attacks the cell wall of some

H2 O 2

bacteria (especially Grampositive cocci).

superoxide radicals
hydrogen peroxide

radicals

OH

hydroxil radicals

NO

toxic radicals

HOCl.

hypochlorus radical

Lactoferrin - an iron-binding protein,

inhibits the

growth of bacteria

Major basic protein (MBP) -

cationic
protein
found
in
eosinophils
and
is
active
principally against parasites.

Bactericidal
permeability
increasing protein (BPI) causes
changes
in
the
permeability of the membranes
of the microorganisms.

Serous
inflammation

Fibrinous
inflammation

Suppurative
(purulent)
inflammation

Catarrhal
inflammation

Haemorrhagic
inflammation

Necrotising
inflammation

Sequelae of Acute
Inflammation
The sequela of acute inflammation depend upon the type of tissue involved
and the amount of tissue destruction, which depend in turn upon the nature
of the injurious agent. The possible outcomes of acute inflammation are:

Resolution
Suppuration
Organization
Chronic inflammation

Chronic inflammation is inflammation of prolonged duration (weeks to years) in

which continuing inflammation, tissue injury, and healing, often by fibrosis, proceed
simultaneously.

In contrast with acute inflammation, which is distinguished by vascular changes,

edema, and a predominantly neutrophilic infiltrate, chronic inflammation is
characterized by a different set of reactions.
Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma
cells
Tissue destruction, largely induced by the products of the inflammatory cells
Repair, involving new vessel proliferation (angiogenesis) and fibrosis

Acute inflammation may progress to chronic inflammation if the acute response cannot
be resolved, either because of the persistence of the injurious agent or because of
Chronicinflammationinthelung,showsthecharacteristichistologicfeatures:collectionofchronicinflammatorycells.
destructionofparenchyma,inwhichnormalalveoliarereplacedbyspaceslinedbycuboidalepithelium(arrowheads);
and replacement by connectivetissue,resultinginfibrosis(arrows).
By contrast, in acute inflammationofthelung(acutebronchopneumonia),neutrophilsfillthealveolarspacesand
bloodvesselsarecongested.

Chronic Inflammatory Cells and Mediators

Macrophages, the dominant cells of chronic inflammation

Lymphocytes . They are mobilized in the setting of any specific immune

stimulus (i.e., infections) as well as nonimmunemediated inflammation

(e.g., due to ischemic necrosis or trauma), and are the major drivers of
inflammation in many autoimmune and other chronic inflammatory diseases.

Other cells:

Eosinophils - characteristically found in inflammatory sites around

parasitic infections and as part of immune reactions mediated by IgE,

typically associated with allergies.

Mast cells - sentinel cells widely distributed in connective tissues

throughout the body, and they can participate in both acute and chronic
inflammatory responses.

Pathways of Macrophage activation.

Different stimuli activate monocytes/macrophages to develop into functionally distinct

populations.

Classically activated macrophages are induced by microbial products and cytokines,

particularly IFN-, and are microbicidal and involved in potentially harmful
inflammation.

Alternatively activated macrophages are induced by IL-4 and IL-13, produced by TH2 cells
(a helper T cell subset) and other leukocytes, and are important in tissue repair and
fibrosis.

Macrophages initiate the process of tissue repair and are involved

in scar formation and fibrosis.
Macrophages secrete mediators of inflammation, such as:
- Cytokines (TNF, IL-1, chemokines, and others) and
- Eicosanoids
These cells are therefore central to the initiation and propagation of all
inflammatory reactions.
Macrophages display antigens to T lymphocytes and respond to signals from T
cells, thus setting up a feedback loop that is essential for defense against
many microbes by cell mediated immune responses.

Lymphocytes

are mobilized in the setting of any specific immune stimulus (i.e.,

infections) as well as nonimmunemediated inflammation (e.g., due to ischemic necrosis or

trauma), and are the major drivers of inflammation in many autoimmune and other chronic
inflammatory diseases.

In the tissues, B lymphocytes may develop into plasma cells, which secrete antibodies, and
CD4+ T lymphocytes are activated to secrete cytokines.

By virtue of cytokine secretion, CD4+ T lymphocytes promote inflammation and influence the
nature of the inflammatory reaction.

There are three subsets of CD4+ helper T cells that secrete different sets of cytokines and elicit
different types of inflammation:
-

TH1 cells produce the cytokine IFN-, which activates macrophages in the classical pathway.

TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are
responsible for the alternative pathway of macrophage activation.

TH17 cells secrete IL-17 and other cytokines that induce the secretion of chemokines
responsible for recruiting neutrophils and monocytes into the reaction.