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. The mediators of defense include phagocytic leukocytes, antibodies, and complement
proteins. Most of these normally circulate in the blood, where they are sequestered so they cannot damage
normal tissues but can be rapidly recruited to any site in the body.

The typical inflammatory reaction develops through a series of sequential steps:

• The offending agent, which is located in extravascular tissues, is recognized by host cells and
molecules.

• Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent
is located.

• The leukocytes and proteins are activated and work together to destroy and eliminate the offending
substance.

• The reaction is controlled and terminated.

• The damaged tissue is repaired.

SIGNS OF INFLAMMATION

The Roman writer Celsus in 1st century A.D. named the famous 4 cardinal signs of inflammation as:

i) rubor (redness);
ii) tumor (swelling);
iii) calor (heat);
iv) dolor (pain)
v) functio laesa (loss of function).
TYPES OF INFLAMMATION

Depending upon the defense capacity of the host and duration of response, inflammation can be classified
as acute and chronic.

ACUTE INFLAMMATION

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, and

(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and
their activation to eliminate the offending agent.

Its mechanism is divided into two

 Vascular events
 Cellular events

VASCULAR EVENTS

Alteration in the microvasculature (arterioles, capillaries and venules) is the earliest response to tissue
injury.

Haemodynamic change

1. Irrespective of the type of cell injury, immediate vascular response is of transient vasoconstriction
of arterioles.
2. Next follows persistent progressive vasodilatation.
3. Progressive vasodilatation, in turn, may elevate the local hydrostatic pressure resulting in
transudation of fluid into the extracellular space. This is responsible for swelling at the local site
of acute inflammation.
4. Slowing or stasis of microcirculation
5. Stasis or slowing is followed by leucocytic margination or peripheral orientation of leucocytes
(mainly neutrophils) along the vascular endothelium.

TRIPLE RESPONSE

Red line appears within a few seconds after stroking and is due to local vasodilatation of capillaries and
venules.

Flare is the bright reddish appearance or flush surrounding the red line and results from vasodilatation of
the adjacent arterioles.

Wheal is the swelling or oedema of the surrounding skin occurring due to transudation of fluid into the
extra vascular space.
Altered Vascular Permeability

i) Contraction of endothelial cells

The endothelial cells develop temporary gaps between them due to their contraction resulting in
vascular leakiness. It is mediated by the release of histamine, bradykinin and other chemical
mediators. The response begins immediately after injury, is usually reversible, and is for short
duration (15-30 minutes).

ii) Mild endothelial damage

there is structural re-organisation of the cytoskeleton of endothelial cells that causes reversible
retraction at the intercellular junctions or mild form of endothelial damage. This change affects
venules and capillaries and is mediated by cytokines such as interleukin-1 (IL-1) and tumour necrosis
factor (TNF)-a. The onset of response occurs after delay of 4-6 hours.

iii) Direct injury to endothelial cells

Direct injury to the endothelium causes cell necrosis and appearance of physical gaps at the sites of
detached endothelial cells. Process of thrombosis involving platelets and fibrin is initiated at the site of
damaged endothelial cells. The change affects all levels of microvasculature (venules, capillaries and
arterioles).

iv) Leucocyte mediated endothelial injury

Adherence of leucocytes to the endothelium at the site of inflammation may result in activation of
leucocytes. The activated leucocytes release proteolytic enzymes and toxic oxygen species which may
cause endothelial injury and increased vascular leakiness.

v) Leakiness in neovascularization

In addition, the newly formed capillaries under the influence of vascular endothelial growth factor
(VEGF) during the process of repair and in tumours are excessively leaky.

CELLULAR EVENTS

The cellular phase of inflammation consists of 2 processes:

1. exudation of leucocytes; and

2. phagocytosis.

Exudation of Leucocytes

The escape of leucocytes from the lumen of micro vasculature to the interstitial tissue is the most
important feature of inflammatory response. In acute inflammation, polymorphonuclear neutrophils
(PMNs) comprise the first line of body defense, followed later by monocytes and macrophages.
 1. CHANGES IN THE FORMED ELEMENTS OF BLOOD

In the early stage of inflammation, the rate of flow of blood is increased due to vasodilatation. But
subsequently, there is slowing or stasis of bloodstream.

2. ROLLING AND ADHESION

Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cells lining the
vessel wall (rolling phase). The following cell adhesion molecules (CAMs) bring about rolling and
adhesion phases:

Selectins These are a group of CAMs expressed on the surface of activated endothelial cells. Their
role is to recognise and bind to glycoproteins and glycolipids on the cell surface of neutrophils. There
are 3 types of selectins:

P – Selectin

E – Selectin

L – Selectin

Integrins These are a family of endothelial cell surface proteins. At the same time the receptors for
integrins on the neutrophils are also stimulated. This process brings about firm adhesion between
leucocyte and endothelium.

3. EMIGRATION

After sticking of neutrophils to endothelium, the neutrophils lodged between the endothelial cells and
basement membrane cross the basement membrane by damaging it locally with secreted collagenases and
escape out into the extravascular space; this is known as emigration.

4. CHEMOTAXIS

The transmigration of leucocytes after crossing several barriers (endothelium, basement memb rane, peri
vascular myofibroblasts and matrix) to reach the interstitial tissues is a chemotactic factor-mediated
process called chemotaxis.

PHAGOCYTOSIS

Phagocytosis is defined as the process of engulfment of solid particulate material by the cells (cell-
eating). The cells performing this function are called phagocytes.

Neutrophils and macrophages on reaching the tissue spaces produce several proteolytic enzymes—
lysozyme, protease, collagenase, elastase, lipase, proteinase, gelatinase, and acid hydrolases. These
enzymes degrade collagen and extracellular matrix.

Phagocytosis of the microbe by polymorphs and macrophages involves the following 3 steps

1. Recognition and attachment

2. Engulfment

3. Killing and degradation

1. RECOGNITION AND ATTACHMENT

Phagocytosis is initiated by mannose receptor and scavenger receptor on macrophages which recognise
microorganisms. The process of phagocytosis is further enhanced when the microorganisms are coated
with specific proteins, opsonins, from the serum and the process is called opsonization.

1. IgG opsonin is the Fc fragment of immunoglobulin G.

2. C3b opsonin is the fragment generated by activation of complement pathway
3. Lectins

2. ENGULFMENT

cytoplasmic pseudopods enveloping opsonised particle or microbe in a phagocytic vacuole. phagosome

becomes internalised in the cell and lies free in the cell cytoplasm. The phagosome fuses with one or
more lysosomes of the cell and form bigger vacuole called phagolysosome.

[Link] AND DEGRADATION

A. Intracellular mechanisms:

i) Oxidative bactericidal mechanism by oxygen free radicals

a) MPO-dependent

b) MPO-independent

ii) Oxidative bactericidal mechanism by lysosomal granules

iii) Non-oxidative bactericidal mechanism

B. Extracellular mechanisms

INTRACELLULAR MECHANISMS

i) Oxidative bactericidal mechanism by oxygen free radicals

myeloperoxidase (MPO)

ii) Oxidative bactericidal mechanism by lysosomal granules

In this mechanism, the preformed granule-stored products of neutrophils and macrophages are discharged
or secreted into the phagosome and the extracellular environment. Progressive degranulation of
neutrophils and macrophages along with oxygen free radicals degrades proteins i.e. induces proteolysis.

iii) Nonoxidative bactericidal mechanism

Granules. Some of liberated lysosomal granules (lipases, proteases) do not kill by oxidative damage but
cause lysis of microbe within phagosome.

Nitric oxide. Nitric oxide is a reactive free radical similar to oxygen free radicals which is formed by
nitric oxide synthase.

B. EXTRACELLULAR MECHANISMS

i) Granules Degranulation of macrophages and neutrophils.

ii) Immune mechanisms.

MEDIATORS OF INFLAMMATION

Mediators of inflammation have some common properties

1) These mediators are released either from the cells or are derived from plasma proteins.
2) All mediators are released in response to certain stimuli.
3) Mediators act on different targets.
4) Range of actions of different mediators are: increased vascular permeability, vasodilatation,
chemotaxis, fever, pain and tissue damage.
5) Mediators have short lifespan after their release.

There are two types.

1) Cell derived mediators

2) Plasma protein derived mediators.

I. Cell-derived Mediators

1. VASOACTIVE AMINES

i) Histamine It is stored in the granules of mast cells, basophils and platelets. The main actions of
histamine are: vasodilatation, increased vascular (venular) permeability, itching and pain.

ii) 5Hydroxytryptamine (5HT or serotonin) It is present in tissues like chromaffin cells of GIT, spleen,
nervous tissue, mast cells and platelets,

2. ARACHIDONIC ACID METABOLITES (EICO SANOIDS)

 Prostaglandins (PGD2, PGE2). PGD2 and PGE2 act on blood vessels and cause increased venular
permeability, vasodilatation and bronchodilatation.
 Thromboxane A2 (TXA2). Platelets contain the enzyme thromboxane synthetase and hence the
metabolite, thromboxane A2, formed is active in platelet aggregation.
 Prostacyclin (PGI2). PGI2 induces vasodilatation, broncho dilatation and inhibits platelet
aggregation.
 5-HETE (hydroxy compound), an intermediate product, is a potent chemotactic agent for
neutrophils.
 Leukotrienes (LT) have common actions by causing smooth muscle contraction and thereby
induce vasoconstriction, broncho constriction and increased vascular permeability.

3. LYSOSOMAL COMPONENTS
i) Granules of neutrophils
 Myeloperoxidase causes oxidative lysis by generation of oxygen free radicals, acid hydrolases act
within the cell to cause destruction of bacteria in phagolysosome.

Proteases attack on the extracellular constituents such as basement membrane, collagen, elastin,
cartilage etc. results in harmful tissue destruction

4. PLATELET ACTIVATING FACTOR (PAF)

i) increased vascular permeability

ii) vasodilatation in low concentration

ii) bronchoconstriction;
iii) adhesion of leucocytes to endothelium;
iv) Chemotaxis’

[Link]

Interleukins, Tumor Necrotic factors, Interferons

II. Plasma Protein-derived Mediators (Plasma Proteases)

1. THE KININ SYSTEM

Bradykinin acts in the early stage of inflammation and its effects include: i) smooth muscle
contraction; ii) vasodilatation; iii) increased vascular permeability; and iv) pain.

2. THE CLOTTING SYSTEM

Factor Xlla initiates the cascade of the clotting system resulting in formation of fibrinogen which is
acted upon by thrombin to form fibrin and fibrinopeptides. The actions of fibrinopeptides in
inflammation are: i) increased vascular permeability; ii) chemotaxis for leucocyte; and iii)
anticoagulant activity.

3. THE FIBRINOLYTIC SYSTEM

Plasminogen activator acts on plasminogen present as component of plasma proteins to form plasmin.

The actions of plasmin in inflammation are as follows:

i) activation of factor XII to form prekallikrein activator that stimulates the kinin system to
generate bradykinin;
ii) splits off complement C3 to form C3a which is a permeability factor;
iii) degrades fibrin to form fibrin split products which increase vascular permeability and are
chemotactic to leucocytes.

4. THE COMPLEMENT SYSTEM

Complement system on activation by either of these two pathways yields activated products which
include anaphylatoxins (C3a, C4a and C5a), and membrane attack complex (MAC) i.e. C5b,C6,7,8,9.

The actions of activated complement system in inflammation are as under:

 C3a, C5a, C4a (anaphylatoxins) activate mast cells and basophils to release of histamine, cause
increased vascular permeability causing oedema in tissues, augments phagocytosis.
 C3b is an opsonin.
 C5a is chemotactic for leucocytes.
 Membrane attack complex (MAC) (C5b-C9) is a lipid dissolving agent and causes holes in the
phospholipid membrane of the cell