2. Bob Young A507 The Biology of Disease CH0576 Module Tutor: Dr D. Holmes Introduction to Cell Injury

3. Bob Young A507 Introduction  Pathology: “…the study of structural and functional abnormalities that are expressed as diseases of organs or systems.” oThe first half of this double module will concentrate on causes and mechanisms of cellular and subcellular damage. o The second half will tend to concentrate on dieases of organ systems, as a consequence of this damage.

4. Bob Young A507 Causes of Cellular Injury oBroadly divided into the following major groups:- oHypoxia oChemicals & Drugs oPhysical Agents oMicrobiological agents oImmune Mechanisms  Genetic Defects oNutritional Imbalances o- Deficiencies o- Excesses oAgeing

5. Bob Young A507 Hypoxia oA reduction in the oxygen supply to cells and tissues. oIt 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

6. Bob Young A507 Chemicals & Drugs oMany chemicals and drugs interfere with cell membrane permeability or the functioning of vital enzymes within the cell. oVery little is known of pathways of damage to cells, by some chemicals. o Generally chemicals or drugs have a specific target within the body which is damaged.

7. Bob Young A507 Chemicals & Drugs II oSelectivity of damage reflects various cell populations involved in the handling of the chemical. oBarbiturates are degraded in the liver and hence can cause liver damage. oMercuric chloride is absorbed by the stomach and excreted via the kidneys and colon - the main targets in poisoning.

8. Bob Young A507 Physical Agents oA wide range of physical agents have an effect on body cells:- - extremes of heat and cold - trauma - radiation - electrical energy - alteration in pH levels.

9. Bob Young A507 Microbiological Agents oThis wide ranging group of organisms consists of:- - Viruses - Bacteria - Fungi - Microscopic parasites oThey are able to cause damage to cells and tissues via an assortment of routes.

10. Bob Young A507 Immunological Agents oPrimarily the immune system has beneficial effects upon the host, protecting against potentially harmful infective organisms. oThe immune system itself can be source of damage to the host: - Hypersensitivities - Autoimmunity oMechanisms discussed in CH054.

11. Bob Young A507 Genetic Defects oThese can manifest themselves in overt abnormalities or in subtle alterations in protein structure, and hence function. oE.g. ranging from Down’s Syndrome to a single amino acid substitution, as found in HbS in Sickle Cell Anaemia.

12. Bob Young A507 Nutritional Imbalances oThese are obviously more common in underprivileged and less well developed areas of the world. oProtein and vitamins are the commonest type of the nutritional deficiencies. oAs 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).

13. Bob Young A507 Ageing o Although not really a pathological process there are changes in both cell function and morphology associated with advancing years. o A range of theories of ageing have been proposed to account for the changes seen in aged individuals.

14. Bob Young A507 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

15. Bob Young A507 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.

16. Bob Young A507 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.

17. Bob Young A507 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.

18. Bob Young A507 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’.

19. Bob Young A507 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.

20. Bob Young A507 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.

21. Bob Young A507 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.

22. Bob Young A507 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.

23. Bob Young A507 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’

24. Bob Young A507 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.

25. Bob Young A507 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.

26. Bob Young A507 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.

27. Bob Young A507 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

28. Bob Young A507 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.

29. Bob Young A507 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.

30. Bob Young A507 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.

31. Bob Young A507 Cell Stress Proteins  Manageable levels of injury/stress allows the cell time to undergo cellular adaptation: –Atrophy –Hypertrophy –Hyperplasia –Metaplasia –Dysplasia.