Inflammation is part of the body’s defence and healing process, so it is generally beneficial to the

body unless injuries persist and create complications.

Inflammation occurs in response to mild/sublethal injury to connective tissue. Inflammation also

follows necrosis as the process of replacing necrotic tissue with scarred tissue if the person survives.

Inflammation can be:

Sub-acute

Acute – lasts for hours or days, and represents a series of reactions involving blood and
connective tissue cells

Chronic – long lasting, for weeks-months-years

Inflammation is caused by fluid coming from the vessels that floods the interstitial space and carries
proteins that are important in the renewal process of the injured cells.

The first most common inflammations are respiratory (>50%), second most common are urinary.

Rhinitis – inflammation of the nasal mucosa; sinusitis, laryngitis, tracheitis, trachea-bronchitis,

bronchitis, bronchiolitis – inflammation of the bronchioles, pneumonia – inflammation of the lungs
at the alveolus sac level and terminal bronchioles known as broncho-pneumonia, pleuritis –
inflammation of the pleura and pleural space.

5 Signs of acute inflammation – also known as the “5 cardinal signs”, the first 4 being defined in the
1st century by Aulus Cornelius Celsus

HEAT

REDNESS

PAIN

SWELLING

The 5th sign was defined in the 19th century by Rudolf Virchow – the father of cellular pathology

LOSS OF FUNCTION

e.g. in case of burn injury to the skin there might the loss of function of sebaceous or sweat glands in
the dermis

ACUTE INFLAMMATION

What happens in acute inflammation so that we see those signs? Let’s take the example of a small
injury to the skin – a scratch with the nail

1. First, we see a transient white line; this is caused by a transient vasoconstriction of

arterioles which in turn causes blanching of the area (not always seen); when this happens
cells get disrupted e.g. mast cells in the local tissue (basophils when they come from the
blood stream), basophils and platelets release histamines; mast cells are a very important
mediator of acute inflammation and also a vasodilator
2. Histamine release causes sustained vasodilation of arterioles/venules and hyperaemia
(increased blood flow to the area) causing redness and heat – the signs of inflammation.
Blood flooding an injured area is important in the healing process because it brings oxygen,
 nutrients and cells such as neutrophils and monocytes that release pyrogens increasing local
body temperature that kills pathogens
3. Due to vasodilation, there is an increase in vascular permeability which allows fluid and
proteins (and sometimes cells depending on the type of injury) to escape into the tissue
space causing the swelling of the tissue. This fluid, that moves through is called an
inflammatory exudate.

Histamines stimulate the opening of inter-endothelial cell junctions and also release Ca to
control actin/myosin contraction – remember that the blood vessels have smooth muscle
cells which also have to be opened up.
HISTAMINES ARE INVOLVED IN 1, 2, 3 – triple response of Lewis
Pallor – vasoconstriction
Redness – vasodilation
Swelling - exudate

The extravasated fluid accounts for the swelling, pain and loss of function signs. The
increase of the interstitial fluid causes an increase in pressure stimulating nerve ending to
perceive pain. Also, the increase in tissue pressure leads to a loss of function in those tissue.
There are other mediators apart from histamine: complement components, arachidonic acid
metabolites, kinins and other amines like adrenaline

Exudates form easily in porous vascular endothelium such as in the spleen, liver that have
sinusoidal epithelium, and even bone marrow. In tissues with fenestrated epithelium
(kidney, glandular organs, GIT) there is also opportunity in case of injury for the formation of
inflammatory exudates. But tissues with tight junctions like those in the BBB, muscle and
skin, histamine is required to open up the junctions so that fluid can move through.

3 types of vascular endothelium

Sinusoidal Fenestrated Continuous

Physical forces acting across capillary walls (Starling forces) cause fluid to move form within
vessels to extravascular space and vice versa thus forming tissue fluid – TRANSUDATE. This
forces actually determining how much fluid is lost to the extravascular space, maintaining a
balance between vascular and extravascular normal tissue. The transudate is return to
circulation via lymphatics.

If the protein content of the fluid is very low it will disturb this equilibrium causing more
fluid to move into tissue space than normal.

Exudate contain higher protein e.g. fibrinogen concentration compared to transudate which
explains why the exudate can extravasate.

As part of the exudate, apart from fluid, electrolytes and proteins there are also cells coming
through depending on the type of injury
 There are 4 types of exudates:

Serous inflammatory exudate e.g. when you get skin blisters when you touch a hot
plate

Low in protein level and very little leukocytic emigration e.g. skin blister

Fibrinous exudate
High in protein level (e.g. fibrinogen – soluble in blood, which converts to
fibrin – insoluble and sticky in tissue)
e.g. too much urea can go to the heart and lungs and cause fibrinous
pericarditis and pleurisy; due to injury an exudate rich in fibrinogen is
formed which accumulates in the pleural space or pericardial space; this can
be heard with a stethoscope – friction rub and it represents that the person
has a fibrinous type of inflammation

Suppurative exudate (suppuration = pus, pus is not just liquefactive necrosis but
also lots of neutrophils)

Lots of white blood cells that move through with the fluid usually as a
resul\of an infection e.g. meningitis, starts of as a respiratory infection, goes
into the blood then moves into the brain to develop meningitis, so in the
meninges we see this suppuratives exudate

Haemorrhagic exudate

Red blood cells move through with the fluid; it is a red exudate directly
damaging vessels and all blood components (fluid, proteins, RBC, WBC) leak
out into tissue space e.g. bleeding peptic ulcer – ulceration and erosion of
the lining of the stomach which damage blood vessels

There is only that much exudate that can form, eventually the endogenous mediators will wear off,
their action will subside which will allow that exudate to stop forming. The arterioles will gradually
constrict as the histamines wear off. If there are injured vessels platelets will come along and plug up
the leaking vessel. The tissue stops expanding under the pressure of the exudate, its distensibility is
limited. And lymphatic drainage is increased, fluid goes back into the thoracic duct, reabsorbed via
the inferior vena cava into the venous system.

ACUTE INFLAMMATION SUMMARY – steps 1, 2, 3

The exudate has formed, the fluid containing potentially some leukocytes (depending on what
caused the injury) has now flown from the vessel space into the tissue space.

4. This means that now there is a high concentration of cellular elements in the blood at the
site of injury, causing a decrease in the velocity of blood at that site. As a result the blood
comes to a stop – Stasis and the cells collide to one another and adhere to the vessel wall.
Normally cells in the blood have a laminal flow – in the middle, only the plasma lubricates
the wall.
5. If we get stasis of blood flow the white blood cells in particular will start lining, adhering to
the vessel wall. This is known as Margination. As the cells adhere to the vessels they make
their way through closed inter-endothelial junctions, digest the basement membrane and
escape from circulation to the tissue. This is known as Diapedesis – the formation of an
 infiltrate by extravasation of cells into the tissue space. This is part of a natural healing
process as we want these cells at the site of injury to phagocytose all the debris present at
the injured area.

Cellular aspect of acute inflammation

Infiltrate – post exudate formation, is made up of only leukocytes (not the fluid).

The predominant component of the infiltrate is the neutrophil, which is a phagocytic cell
containing endogenous pyrogens, chemotactic factors that attract other cells and also
vasodilators. Other cells present are macrophages (monocytes in blood) and some lymphocytes.

6. The site of injury create a chemical gradient (toxins, chemical debris, bacteria) by which the
infiltrates travel down to the site of injury. This movement is called Chemotaxis.
The accumulation of cells creates pressure and this cause pain and loss of function.
7. Once at the site of injury, leukocytes start to the process of Phagocytosis – ingestion of
necrotic debri, bacteria and even mop up some of the exudate and toxins.

SEQUELAE OF ACUTE INFLAMMATION

A sequela is any possible result, complication or conclusion of a pathological process.

There are 4 different sequelae for acute inflammation (AI):

1) Resolution: is complete restoration of normal structure and function of tissue e.g. mild burn
with a blister – eventually the fluid resolves and blister goes away

Most pneumonia is caused by streptococcus pneumoniae which causes and acute

inflammatory state at the level of the alveolar sacs and ducts.

a. So, what we see in the capillaries lining the alveolar wall is an increase in blood flow
– hyperaemia, during the first stage of the infection, 1-2 days after contracting the
bug. We also see a consolidation of the lungs – solid looking. And we see this
process throughout an entire lobe(s) – diffuse distribution.

If effectively treated with antibiotics at this stage usually there is Resolution. If there
is no resolution the patient might die due to dyspnoea – difficulty breathing.

b. In the next stage of the infection the lung start to look a lot like the liver – Red
hepatisation, after 2-4 days (the red exudates moves into the tissue space)

Effective treatment at this stage will help the lung to form an infiltrate – white blood
cells moving into the tissue to mop up the red exudate, forming Grey hepatisation,
4-8 days after infection. If the patient is not treated, there is a crisis situation by 8fth
day – patient dies.

So, the usual outcome of pneumonia is complete resolution, no necrosis, no pass

formation.

2) Another example is a situation where an acutely inflamed tissue gets infected later on with
pyogenic bacteria and an Abscess forms (pus filled cavity) which is known as suppuratives
exudate. The pus as we know contains necrotic tissue – liquefactive necrosis, composed of
viable or non-viable neutrophils and pyogenic bacteria.
 3) Repair (healing process): if the tissue that has been injured has the capacity to regenerate
(e.g. the epidermis, but the dermis where the hair follicles, sebaceous glads and sweat
glands are they don’t have the capacity to regenerate), will replace the injured tissue with
new tissue. However, the tissue that has cells which can’t regenerate will be replaced with
scar tissue, the process of scaring being called Organization. In some tissue the scar tissue is
fibrotic in other is gliotic, the process being called Fibrosis and Gliosis. So, in the case where
the skin has been injured often a combination of regeneration and organization may occur –
the epidermis regenerates and the dermis undergoes organization.

The newly formed scar tissue, called Granulation tissue consists of fibroblast (or glial cells
when proliferating to the brain) cells which produce collagen, capillaries (angiogenesis – new
vessels sprouting out, old vessels going into the injured area to provide nutritional support
for the healing process) that provide the nutrients and macrophages.

E.g. an example of the repair process is bronchopneumonia – a type of pneumonia that can
be caused by various microorganisms; occurs mainly in children or elderly. It has an acute
course but it is not as clear cut as in the case of lobar pneumonia. In this case part of the
lobe might be showing early signs of acute inflammation – hyperaemia, other part of the
lobe showing red hepatisation and yet other grey hepatisation. The acute inflammation is
localized close to the bronchi and bronchioles hence the patchy consolidation to the lobes,
not a diffused consolidation like in the case of lobar pneumonia. Here there is a lot of
necrosis and scarring formation where as in lobar pneumonia there is no necrosis, no scaring
but complete resolution. If the patient survives the lung will be damaged and it is more likely
to get recurrent infections over the years.

In some cases of organization where the scar tissue is for example in the pleura there is a
possibility of complications. If the fibrinous pleurisy (exudate) is not resolved (by the
inifiltrate) it will be replaced with scar tissue which form permanent adhesion which are
fibrous compromising lung functions which cause difficulty breathing.

CRONIC INFLMMATION

If the inflammation persists and is not able to resolve the infection effectively, it can become chronic
– long standing. If the injury persists, there is constant injury ->> constant inflammation ->> constant
healing of the tissue. A constant response of the immune system also occurs, macrophages are
recruited and certain cytokines being release will attract lymphocytes. The result of this constant
healing process is a large volume of scar tissue.

Chronic inflammation can also occur as a primary response rather than following acute
inflammation.

Chronic inflammation is a different process clinically than AI – it is long lasting and involves diff.
immune mechanisms – T-cells mediated response, B-cells crossing over into tissue to become
plasma cells synthesising antibodies (humoral immunity).

Chronic inflammation is described as being:

Productive – because there is a cellular response rather than an exudative one; the infiltrate
forms from the beginig rather than the exudate

Pleomorphic – due to the different types of cells seen at the same time in the infiltrate –
proinflammatory cells but also lymphocytes: T-cells that produce cytokines (cell mediated
immunity), B-cells that synthesis antibodies (humoral immunity); monocytes that cross over
as macrophages which can differentiate into various types: giant cells and epithelioid cells,
granulocytes (but in small numbers): neutrophils (mostly seen in acute infections),
eosinophils (mostly seen in parasitic infections), basophils (allergic immune reactions).

Macrophages are phagocytic, however if they differentiate into epithelioid cells they acquire
properties specific to cell signalling types and loose the phagocytic function, have the
capacity to synthesis cytokines. Giant cells are fused macrophages with many nuclei These
cells form when foreign substances can’t be digested by macrophages e.g. asbestos fibres in
lung; wood splinter in the skin – the injury will attract macrophages, but because they can’t
digest the wood the cells merge to push the splinter to the surface of the epithelium and
allow for it to shed along with skin cells; specialized bacteria such as mycobacterium species
which have mycolic acid wall – very waxy and the macrophages cannot phagocyte them so
they turn into giant cells and isolate the infection site.

When a giant cells undergoes internal organisation of their nuclei, in a horse shoe shape, the
cell becomes a Langhans giant cell. If the nuclei are organised in a cluster, in the centre of
the cell, the giant cell is called foreign body giant cell.

Forms of Chronic Infections

1) Chronic Fibrous inflammation – the key feature in this type of chronic inflammation is
lots of collagen scar tissue formation
a. e.g. rheumatoid arthritis – obliteration of joints with scar tissue causing
Anchyloses (complication of chronic inflammation) – fusion of joints causing
immobility
b. e.g. chronic duodenal ulcer – chronic ulceration of the lining of the duodenum
causes scar formation which can obliterate duodenum and cause an abnormal
narrowing of the lumen obstructing the passage
c. e.g. stenosis – in rheumatic heart disease the valve of the heart is damaged and
scaring can cause an abnormal narrowing of the opening to the valve
obstructing the flow of blood which could cause back flow or less flow through
2) Chronic Serous Inflammation – an abnormal increased production of serous fluid by a
serous membrane such as the pericardial, pleural, peritoneal and synovial membranes.
This is also called a “cold swelling” not a “hot swelling” like in the case exudate in acute
inflammation.
a. e.g bursitis of the shoulder
3) Chronic suppurative inflammation – an abnormally increased amount of pus production
a. An endurious stimulus persisting will degenerate into a chronic inflammation
e.g. chronic axillary abscess
4) Chronic ulcerative inflammation – a steady progression from an acute ulceration to a
chronic one, the diff. being the depth of damage to the tissue – deep excavation of
tissue in chronic ulcerations
a. e.g. tropical ulcer due to specialized bacterium – Mycobacterium ulcerans
b. e.g. chronic peptic ulcer due to specialized bacterium - Helicobater phylori

chronic peptic ulcer damage to: mucosa ->> submucosa ->> muscularis ->> serosa -
>> perforation of stomach (death)
 If only the mucosa is damaged that is known as an erosion. From submucosa
downward is called ulcer.

5) Chronic granulomatous inflammation – no acute inflammatory response beforehand;

occurs as a primary response to stimuli, characterized by formation of granulomas –
solid tissue nodules; histological analysis will show presence of necrosis, inflammatory
cells and some fibroblasts laying down collagen in tissue.

Granulomas are associated with destruction of tissue caused by specialized bacteria and
also autoantibodies attacking the host tissue.

a. Hansen’s disease (leprosy) caused by Mycobacterium leprae – loss of skin and

nerve tissue (loss of sensation)
b. Tuberculosis caused by mycobacterium tuberculosis

Cellular aspects of Chronic Granulomatous Inflammation

Macroscopically they present as lumps.

Microscopically every granulomatous presents the same structure:

Necrotic tissue in the center

Various types of cells throughout

T-lymphocytes and macrophages

Multinucleated giant cells (Langhans and foreign bodies)

Epithelioid cells

Fibroblasts and collagen at the periphery

In tuberculosis, the centre of granulomas is caseous necrosis but in sarcoidosis they are coagulative
necrosis. They all have the same appearance but the centre of necrosis might be different. In
tuberculosis the granulomas are called specific (tubercle) – cause known, in sarcoidosis are called
non-specific – cause unknown.

Types of Tuberculosis:

1. Tuberculous bronchopneumonia
a. Inhaled mycobacterium tuberculosis lodges in the lungs and produce a full blown
tuberculosis disease, or a granuloma where the bacterium sits dormant and produce
recurrent infections, or the lesions can fully heal and never develop the disease.

If the disease develops into Tuberculous bronchopneumonia, the tubercles (varying

in size) form close to the bronchi and bronchioles, erode airways resulting in spread
of bacteria via bronchi and bronchioles

2. Miliary tuberculosis
a. If the disease develops into Miliary tuberculosis, the tubercles (which are v. small)
form close to the blood vessels, erode the vessels and bacteria escapes into the
blood stream and lymphatic system

In active cases the bacteria is detected with Ziehl-Neelsen stain.

6) Active Chronic Inflammation – a long course of chronic inflammation with episodes of
pronounced symptoms when tissue damage is maximal
4)