Transcript Cellular Basis of Disease

The Biology of Disease
CH0576
Module Tutor: Dr D. Holmes
Introduction to Cell Injury
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Introduction
Pathology: “…the study of structural and
functional abnormalities that are
expressed as diseases of organs or
systems.”
The first half of this double module will
concentrate on causes and mechanisms of
cellular and subcellular damage.
 The second half will tend to concentrate on
dieases of organ systems, as a consequence of
this damage.
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Causes of Cellular Injury
 Broadly divided into
the following major
groups: Hypoxia
 Chemicals & Drugs
 Physical Agents
 Microbiological agents
 Immune Mechanisms
 Genetic Defects
 Nutritional Imbalances
- Deficiencies
- Excesses
 Ageing
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Hypoxia
A reduction in the oxygen supply to
cells and tissues.
It can result from:- a loss of blood flow to the tissues
- inadequate oxygenation of the blood
- a reduction in the oxygen carrying
capacity of the blood
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Chemicals & Drugs
Many chemicals and drugs interfere with
cell membrane permeability or the
functioning of vital enzymes within the cell.
Very little is known of pathways of damage
to cells, by some chemicals.
 Generally chemicals or drugs have a
specific target within the body which is
damaged.
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Chemicals & Drugs II
Selectivity of damage reflects various cell
populations involved in the handling of the
chemical.
Barbiturates are degraded in the liver and
hence can cause liver damage.
Mercuric chloride is absorbed by the
stomach and excreted via the kidneys and
colon - the main targets in poisoning.
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Physical Agents
A wide range of physical agents have
an effect on body cells:- extremes of heat and cold
- trauma
- radiation
- electrical energy
- alteration in pH levels.
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Microbiological Agents
This wide ranging group of organisms
consists of:- Viruses
- Bacteria
- Fungi
- Microscopic parasites
They are able to cause damage to cells and
tissues via an assortment of routes.
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Immunological Agents
Primarily the immune system has beneficial
effects upon the host, protecting against
potentially harmful infective organisms.
The immune system itself can be source of
damage to the host:
- Hypersensitivities
- Autoimmunity
Mechanisms discussed in CH054.
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Genetic Defects
These can manifest themselves in
overt abnormalities or in subtle
alterations in protein structure, and
hence function.
E.g. ranging from Down’s Syndrome to
a single amino acid substitution, as
found in HbS in Sickle Cell Anaemia.
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Nutritional Imbalances
These are obviously more common in
underprivileged and less well developed
areas of the world.
Protein and vitamins are the commonest
type of the nutritional deficiencies.
As important as deficiencies are nutritional
excesses, e.g. animal fats taken in excess
and the link with atherosclerosis (details
to be covered in semester 2).
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Ageing
 Although not really a pathological
process there are changes in both
cell function and morphology
associated with advancing years.
 A range of theories of ageing have
been proposed to account for the
changes seen in aged individuals.
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Cell Survival Requirements
Most vital that a cell possesses a
structural and functional barrier
between the cytosol and potentially
hostile envirinment:– The plasma membrane
• helps maintain a constant internal ionic
composition against large gradients
• Selectively admits some molecules whilst
excluding or actively expelling others.
• Provides a structural envelope to contain cell
constituents
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Cell Survival Requirements
All cells in order to survive must be
able to adapt to adverse environmental
conditions such as changes in:–
–
–
–
–
Temperature
Solute concentrations
Oxygen supply
Presence of noxious agents
pH alterations etc.
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Cell Survival Requirements
If an injury exceeds the adaptive
capacity of the cell it dies.
Cells exposed to sub-lethal injury
have a limited number of cellular
adaptations.
All cells have generally efficient
mechanisms to deal with shifts in
their surrounding conditions.
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The Cell Stress Response
In response to potentially damaging
stimuli cells produce a series of
metabolic changes which are collectively
known as the ‘cell stress response’.
This is a highly conserved biological
response seen throughout the animal
phyla.
This conservation, suggesting that it is
essential to cell survival.
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Cell Stress Proteins
These were originally demonstrated in
fruit fly larvae.
The larvae responded to elevation in
temperature by expressing a range of new
proteins - ‘heat shock proteins’.
These HSPs are produced in response to a
wide range of potentially damaging stimuli hence ‘cell stress proteins’.
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Cell Stress Proteins
The same proteins are produced in
response to damaging stimuli by all
species so far studied - hence a highly
conserved response.
In cell stress the genes which code for
normal structural proteins are turned
down, and there is high expression of
the genes encoding the CSPs.
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Cell Stress Proteins
CSP production is a rapid process which:
– minimises cell damage
– helps to maintain cell viability.
CSPs are only able to protect against a
certain level of damage.
Damage/stress over this threshold will
result in cell degeneration and death:
– irreversibly injured  cell death.
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Adaptations
Only when the environmental changes
are > capacity of the cell to maintain
normal homeostasis does the cell
undergo acute cell injury.
If the injury/insult is removed in
time, or the cell is able to adapt and
withstand the injury, the term
reversible injury is applied.
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Injury Types
Once a reversible injury/assault is
removed the cell regains its full
structural and functional integrity.
If the cell injury/assault is severe
and prolonged, and the adaptive
capacity of the cell is exceeded the
injury becomes irreversible.
The cell will inevitably die.
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Reversible Cell Injury
Acute cell injury can arise from a
variety of causes.
Regardless of the cause, injured cells
are often larger than their normal
counterparts.
Enlargement is due to an increased
water content and is termed ‘hydropic
swelling’
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Hydropic Swelling
Usually a large pale cytoplasm with a
normally positioned nucleus
Number of organelles within the
acutely injured cell remains the same,
they appear more dispersed in the
larger cytoplasm.
Excess fluid also accumulates within
the cisternae of the ER  dilated.
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Hydropic Swelling
This results from an impairment of the
cell volume regulatory processes.
These processes control the ionic
composition of the cell cytoplasm.
– This regulation, for an ion like Na+operates
at 3 levels:
• Plasma membrane itself
• Plasma membrane Na+K+ATPase.
• Supply of ATP to power the above.
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Hydropic Swelling
Injuring agents can potentially interfere
with this regulatory process at a number
of points:
– By making the cell membrane more
permeable to Na+, exceeding the cell’s
capacity to extrude it.
– Direct damage to the Na+K+ pump itself
– By interfering with the cell’s synthesis of
ATP.
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Organelle Changes
Endoplasmic Reticulum:
– the cisternae become distended and
dilated by fluid accumulation.
– Often the membrane bound ribosomes
detach from the surface of the E.R
– The free ribosomes accumulate within
the cytoplasm which gives it a more
granular appearance. R.E.R  S.E.R
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Organelle Changes
Mitochondria:
– Membrane bound organelles.
– Become dilated in some forms of acute
cell injury, especially due to ischaemia.
– Dilation is due to interference with ionic
regulatory mechanisms across the
membranes.
– Matrix within the mitochondria exhibits
a decreased density.
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Organelle Changes
Plasma Membrane:
– Focal extrusions or ‘blebs’ of the
membrane are sometimes seen in acutely
injured cells.
– These may become ‘pinched off’ or lost
from the cell, with the cell remaining
viable.
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Organelle Changes
Nucleolus:
– Acute cell injury is mainly reflected
within the nucleus by changes in the
nucleolus.
– The fibrillar and granular components of
the nucleolus may become separated
from each other.
– Sometimes the granular component
diminishes, leaving an apparently fibrillar
core.
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Cell Stress Proteins
Manageable levels of injury/stress
allows the cell time to undergo cellular
adaptation:
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–
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–
–
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia.
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