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The Biology of DiseaseCH0576

Module Tutor: Dr D. HolmesIntroduction to Cell Injury

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IntroductionPathology: “…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 RequirementsMost 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 ResponseIn 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 ProteinsThese 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 ProteinsCSP 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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AdaptationsOnly 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 SwellingThis 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 SwellingInjuring 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 ChangesMitochondria:

– 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 ChangesNucleolus:

– 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 ProteinsManageable levels of injury/stress

allows the cell time to undergo cellular adaptation:– Atrophy– Hypertrophy– Hyperplasia– Metaplasia– Dysplasia.