Inflammation: Acute

List the cardinal signs of inflammation

SIGNS OF INFLAMMATION. the famous 4 cardinal signs of inflammation are:

● rubor (redness);
● tumor (swelling);
● calor (heat); and
● dolor (pain).
To these, fifth sign functio laesa (loss of function) was later added by Virchow. The word
inflammation means burning.

Define inflammation. Describe the vascular events in inflammation

Inflammation is defined as the local response of living mammalian tissues to injury due to any
agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent,
followed by removal of the necrosed cells and tissues.
TYPES OF INFLAMMATION.
Depending upon the defense capacity of the host and duration of response, inflammation can
be classified as acute and chronic.
A. Acute inflammation is of short duration (lasting less than 2 weeks) and represents the early
body reaction, resolves quickly and is usually followed by healing
B. Chronic inflammation is of longer duration and occurs either after the causative agent of
acute inflammation persists for a long time, or the stimulus is such that it induces chronic
inflammation from the beginning

FATE OF ACUTE INFLAMMATION

The acute inflammatory process can culminate in one of the following outcomes :
1. Resolution. It means complete return to normal tissue following acute inflammation. This
occurs when tissue changes are slight and the cellular changes are reversible e.g. resolution in
lobar pneumonia.
2. Healing. Healing by fibrosis takes place when the tissue destruction in acute inflammation is
extensive so that there is no tissue regeneration. But when tissue loss is superficial, it is
restored by regeneration.
3. Suppuration. When the pyogenic bacteria causing acute inflammation result in severe tissue
necrosis, the process progresses to suppuration. Initially, there is intense neutrophilic infiltration.
Subsequently, mixture of neutrophils, bacteria, fragments of necrotic tissue, cell debris and fibrin
comprise pus which is contained in a cavity to form an abscess. The abscess, if not drained,
may get organised by dense fibrous tissue, and in time, get calcified.
4. Chronic inflammation. Persisting or recurrent acute inflammation may progress to chronic
inflammation in which the processes of inflammation and healing proceed side by side.

Chemical mediators of inflammatio

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 microvasculature 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. The changes leading to migration of leucocytes are as follows:
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.
With stasis, changes in the normal axial flow of blood in the microcirculation take place.
The normal axial flow consists of central stream of cells comprised by leucocytes and RBCs and
peripheral cell-free layer of plasma close to vessel wall.
Due to slowing and stasis, the central stream of cells widens and peripheral plasma zone
becomes narrower because of loss of plasma by exudation. This phenomenon is known as
margination.
As a result of this redistribution, the neutrophils of the central column come close to the vessel
wall; this is known as pavementing.
2. ROLLING AND ADHESION. Peripherally marginated and pavemented neutrophils slowly roll
over the endothelial cells lining the vessel wall (rolling phase).
This is followed by the transient bond between the leucocytes and endothelial cells becoming
firmer (adhesion phase).
The following molecules bring about rolling and adhesion phases:
i) Selectins
ii) Integrins
iii) Immunoglobulin gene superfamily adhesion molecule
3. EMIGRATION. After sticking of neutrophils to endothelium, the former move along the
endothelial surface till a suitable site between the endothelial cells is found where the
neutrophils throw out cytoplasmic pseudopods. Subsequently, 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
Simultaneous to emigration of leucocytes, escape of red cells through gaps between the
endothelial cells, diapedesis, takes place
4. CHEMOTAXIS.
The chemotactic factor-mediated transmigration of leucocytes after crossing several barriers
(endothelium, basement membrane, perivascular myofibroblasts and matrix) to reach the
interstitial tissues is called chemotaxis.
The following agents act as potent chemotactic substances or chemokines for neutrophils: i)
Leukotriene B4 (LT-B4), a product of lipooxygenase pathway of arachidonic acid metabolites ii)
Components of complement system (C5a and C3a in particular) iii) Cytokines (Interleukins, in
particular IL-8) iv) Soluble bacterial products (such as formylated peptides)
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. There are 2 main types of phagocytic
cells:
i) Polymorphonuclear neutrophils (PMNs)
ii) Macrophages.
Neutrophils and macrophages on reaching the tissue spaces produce several proteolyitc
enzymes. These enzymes degrade collagen and extracellular matrix. The microbe undergoes
the process of phagocytosis by polymorphs and macrophages and involves the following 3
steps:
1. Recognition and attachment
2. Engulfment
3. Killing and degradation
1. RECOGNITION AND ATTACHMENT
Phagocytosis is initiated by the expression of surface receptors on macrophages which
recognise microorganisms: mannose receptor and scavenger receptor.
The process of phagocytosis is further enhanced when the microorganisms are coated with
specific proteins, opsonins, from the serum or they get opsonised.
Opsonins establish a bond between bacteria and the cell membrane of phagocytic cell.

2. ENGULFMENT
The opsonised particle bound to the surface of phagocyte is ready to be engulfed. This is
accomplished by formation of cytoplasmic pseudopods around the particle due to activation of
actin filaments beneath cell wall, enveloping it in a phagocytic vacuole. Eventually, the plasma
membrane enclosing the particle breaks from the cell surface so that membrane lined
phagocytic vacuole or phagosome lies internalised and free in the cell cytoplasm. The
phagosome fuses with one or more lysosomes of the cell and form bigger vacuole called
phagolysosome.

3. KILLING AND DEGRADATION

Next comes the stage of killing and degradation of microorganism to dispose it off justifying the
function of phagocytes as scavenger cells. The microorganisms after being killed by
antibacterial substances are degraded by hydrolytic enzymes. However, this mechanism fails to
kill and degrade some bacteria like tubercle bacilli.
Disposal of microorganisms can proceed by following mechanisms:
A. Intracellular mechanisms
B. Extracellular mechanisms
Healing by primary and secondary intention
Healing by First Intention (Primary Union) This is defined as healing of a wound which has the
following characteristics:
i) clean and uninfected;
ii) surgically incised;
iii) without much loss of cells and tissue; and
iv) edges of wound are approximated by surgical sutures.

The sequence of events in primary union are:

1. Initial haemorrhage.
Immediately after injury, the space between the approximated surfaces of incised wound is filled
with blood which then clots and seals the wound against dehydration and infection.
2. Acute inflammatory response. This occurs within 24 hours with appearance of polymorphs
from the margins of incision. By 3rd day, polymorphs are replaced by macrophages.
3. Epithelial changes. The basal cells of epidermis from both the cut margins start proliferating
and migrating towards incisional space in the form of epithelial spurs. A well-approximated
wound is covered by a layer of epithelium in 48 hours.
The migrated epidermal cells separate the underlying viable dermis from the overlying necrotic
material and clot, forming scab which is cast off.
4. Organisation. By 3rd day, fibroblasts also invade the wound area. By 5th day, new collagen
fibrils start forming which dominate till healing is completed. In 4 weeks, the scar tissue with
scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is
formed.
5. Suture tracks. Each suture track is a separate wound and incites the same phenomena as in
healing of the primary wound i.e. filling the space with haemorrhage, some inflammatory cell
reaction, epithelial cell proliferation along the suture track from both margins, fibroblastic
proliferation and formation of young collagen. When sutures are removed around 7th day, much
of epithelialised suture track is avulsed and the remaining epithelial tissue in the track is
absorbed. However, sometimes the suture track gets infected (stitch abscess), or the epithelial
cells may persist in the track (implantation or epidermal cysts).

Healing by Second Intention (Secondary Union)

This is defined as healing of a wound having the following characteristics:
i) open with a large tissue defect, at times infected;
ii) having extensive loss of cells and tissues; and
iii) the wound is not approximated by surgical sutures but is left open.
The basic events in secondary union are similar to primary union but differ in having a larger
tissue defect which has to be bridged. Hence, healing takes place from the base upwards as
well as from the margins inwards. The healing by second intention is slow and results in a large,
at times ugly, scar as compared to rapid healing and neat scar of primary union.
The sequence of events in secondary union are:
1. Initial haemorrhage. As a result of injury, the wound space is filled with blood and fibrin clot
which dries.
2. Inflammatory phase. There is an initial acute inflammatory response followed by appearance
of macrophages which clear off the debris as in primary union.
3. Epithelial changes. As in primary healing, the epidermal cells from both the margins of wound
proliferate and migrate into the wound in the form of epithelial spurs till they meet in the middle
and re-epithelialise the gap completely. However, the proliferating epithelial cells do not cover
the surface fully until granulation tissue from base has started filling the wound space. In this
way, preexisting viable connective tissue is separated from necrotic material and clot on the
surface, forming scab which is cast off. In time, the regenerated epidermis becomes stratified
and keratinised.
4. Granulation tissue. Main bulk of secondary healing is by granulations. Granulation tissue is
formed by proliferation of fibroblasts and neovascularisation from the adjoining viable elements.
The newly-formed granulation tissue is deep red, granular and very fragile. With time, the scar
on maturation becomes pale and white due to increase in collagen and decrease in vascularity.
5. Wound contraction. Contraction of wound is an important feature of secondary healing, not
seen in primary healing. Due to the action of myofibroblasts present in granulation tissue, the
wound contracts to one-third to onefourth of its original size.
6. Presence of infection. Bacterial contamination of an open wound delays the process of
healing due to release of bacterial toxins that provoke necrosis, suppuration and thrombosis.
Surgical removal of dead and necrosed tissue, debridement, helps in preventing the bacterial
infection of open wounds.
Factors Influencing Healing
Two types of factors influence the wound healing: those acting locally, and those acting in
general.
A. LOCAL FACTORS:
1. Infection is the most important factor acting locally which delays the process of healing.
2. Poor blood supply to wound slows healing e.g. injuries to face heal quickly due to rich blood
supply while injury to leg with varicose ulcers having poor blood supply heals slowly.
3. Foreign bodies including sutures interfere with healing and cause intense inflammatory
reaction and infection.
4. Movement delays wound healing.
5. Exposure to ionising radiation delays granulation tissue formation.
6. Exposure to ultraviolet light facilitates healing.
7. Type, size and location of injury determines whether healing takes place by resolution or
organisation.
B. SYSTEMIC FACTORS:
1. Age. Wound healing is rapid in young and somewhat slow in aged and debilitated people due
to poor blood supply to the injured area in the latter.
2. Nutrition. Deficiency of constituents like protein, vitamin C (scurvy) and zinc delays the wound
healing.
3. Systemic infection delays wound healing.
4. Administration of glucocorticoids has anti-inflammatory effect.
5. Uncontrolled diabetics are more prone to develop infections and hence delay in healing.
6. Haematologic abnormalities like defect of neutrophil functions (chemotaxis and
phagocytosis), and neutropenia and bleeding disorders slow the process of wound healing.
Acute inflammatory response by the host to any agent is a continuous process but for the
purpose of discussion, it can be divided into following two events: I. Vascular events. II. Cellular
events.
VASCULAR EVENTS (Haemodynamic Changes and Altered Vascular Permeability)
1. Haemodynamic Changes:
The earliest features of inflammatory response result from changes in the vascular flow and
calibre of small blood vessels in the injured tissue. The sequence of these changes is as under:
1. Irrespective of the type of injury, immediate vascular response is of transient
vasoconstriction of arterioles.
2. Next follows persistent progressive vasodilatation which involves mainly the arterioles,
but to a lesser extent, affects other components of the microcirculation like venules and
capillaries. It is responsible for redness and warmth at the site of acute inflammation.
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 follows which causes increased concentration of
red cells, and thus, raised blood viscosity.
5. Stasis or slowing is followed by leucocytic margination or peripheral orientation of
leucocytes (mainly neutrophils) along the vascular endothelium. The leucocytes stick to
the vascular endothelium briefly, and then move and migrate through the gaps between
the endothelial cells into the extravascular space. This process is known as emigration.

The features of haemodynamic changes in inflammation are best demonstrated by the

Lewis experiment. The reaction is known as Triple response or red line response
consisting of the following:
i) Red line appears within a few seconds following stroking and is due to local
vasodilatation of capillaries and venules.
ii) Flare is the bright reddish appearance or flush surrounding the red line and results
from vasodilatation of the adjacent arterioles.
iii) Wheal is the swelling or oedema of the surrounding skin occurring due to transudation
of fluid into the extravascular space. These features, thus, elicit the classical signs of
inflammation—redness, heat, swelling and pain.
 2. Altered Vascular Permeability
In and around the inflamed tissue, there is accumulation of oedema fluid in the interstitial
compartment which comes from blood plasma by its escape through the endothelial wall
of peripheral vascular

Granuloma
Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in diameter, composed
predominantly of collection of modified macrophages called epithelioid cells, and rimmed at the
periphery by lymphoid cells. The word ‘granuloma’ is derived from granule meaning
circumscribed granule-like lesion, and -oma which is a suffix commonly used for true tumours
but here it indicates a localised inflammatory mass or collection of macrophages.

Leprosy
Leprosy is a chronic non-fatal infectious disease affecting mainly the cooler parts of the body
such as the skin, mouth, respiratory tract, eyes, peripheral nerves, superficial lymph nodes and
testis.
Causative Organism
The disease is caused by Mycobacterium leprae which closely resembles Mycobacterium
tuberculosis but is less acid-fast. The organisms in tissues appear as compact rounded masses
(globi) or are arranged in parallel fashion like cigarettes-in-pack.
Leprosy is broadly classified into 2 main types: Lepromatous type representing low resistance;
and Tuberculoid type representing high resistance.