MoD S1+2 - Cell Injury Flashcards Preview

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Flashcards in MoD S1+2 - Cell Injury Deck (78)
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1

What is the difference in cell response to mild versus severe changes in environment?

What if the cell cannot respond appropriately?

Cells can maintain homeostasis when subject to mild changes

Cells must undergo physiological and morphological changes to attempt to stay viable in the face of severe change

If the cell cannot respond appropriately (have reached the limits of their adaptive response) they show evidence or reversible injury or irreversible injury and death

2

What are the major causes of cell injury?

Hypoxia
Physical agents
Chemical agents and drugs
Microorganisms
Immune mechanisms
Dietary insufficiency or excess
Genetic abnormalities

3

What is the result of hypoxia in general terms?

Results in decreased aerobic respiration (although glycolytic respiration can continue)

If this is persistent this can cause Atrophy, cell injury or cell death

4

What are the 4 major types of hypoxia?

Give a brief description and example of each

Hypoxaemic:
Arterial pO2 is low E.g. Reduced inspired PO2 at altitude

Anaemic:
Decreased ability for haemoglobin to carry O2 E.g. anaemia, CO poisoning

Ischaemic:
Interruption to blood supply E.g. Vessel blockage

Histiocytic: Inability to utilise O2 in cells due to disabled oxidative phosphorylation E.g. Cyanide poisoning

5

What is meant by Ischaemia and what causes it?

Loss of blood supply caused by:

Reduced arterial supply (obstruction of artery, hypotension)

Reduced venous drainage

6

Why does Ischaemia cause more severe damage than other forms of hypoxia?

Reduced supply of oxygen AND respiratory substrates E.g. Glucose leads to damage occuring more rapidly and more severe damage than hypoxia

7

How does the length of time cells can tolerate hypoxia vary? Give examples

Differs greatly between cell types

Eg. Some neurones can only tolerate minutes, while fibroblasts can tolerate a number of hours

8

What occurs during reversible hypoxic injury?

Hint: One direct result of hypoxia leads to 3 main effects of this, each with their own concequences

As the cell becomes deprived of oxygen, there is a decrease in ATP production by oxidative phosphorylation.

When ATP concentrations fall to 5-10% of normal concentrations, cellular process are interrupted:

- Loss of Na+/K+ pump activity causing intracellular Na+ concentration to rise causing swelling. Ca2+ also enters the cell and damages cellular components

- Cell switches to anaerobic glycolysis for energy resulting in reduced pH intracellularly, low pH affects many enzymes, chromatin clumping is also seen

- Ribosomes detach from RER and protein synthesis is disrupted, this results in accumulations of fat and denatured proteins in the cell

9

When does cell injury progress from reversible to irreversible?

Not really known/not well understood

10

What is the result of irreversible hypoxic injury?

Hint: Don't go into detail on the effects of Calcium

Usually appears as necrosis

Profound disturbances in membrane integrity

Massive cytosolic accumulation of Ca2+

Intracellular substances leak out into circulation (E.g. Enzymes such as transaminases from liver cells) and can indicate cellular damage is occuring

11

How is Ca2+ involved in irreversible cell damage?

What is the effect of Ca2+ accumulation on a cell experiencing irreversible damage?

Ca2+ enters cells across the damaged plasma membrane and is released from stores in the RER and mitochondria causing Cytosolic build-up

Activates a host of enzymes such as:

ATPases - reduce ATP concentration further

Phospholipases - Cause further membrane damage

Proteases - Breakdown of membrane and cytoskeletal proteins

Endonucleases - Breakdown DNA

Causes leakage of lysosymes (by causing enzymes to damage their membranes) and hence further cell damage

12

What is Ischaemia-reperfusion injury?

Tissue injury can be worse if blood flow is restored and the tissue is not yet necrotic

This may be due to:

- Increased production of ROS with reoxygenation

- Increased number of neutrophils causing more inflammation and injury

- Delivery of complement proteins and activation of complement pathway

13

Give examples of physical agents that may cause cell damage

Direct Trauma
Extreme temperatures
Sudden change in atmospheric pressure
Electric currents
Radiation

14

Give examples of chemical agents and drugs that might cause cell damage

Glucose or salt in hypertonic solutions
O2 at high concentrations
Poisons
Insecticides
Herbicides
Asbestos
Alcohol
Illicit drugs
Therapeutic drugs

15

How might immune mechanisms lead to cell damage?

Hypersensitivity reactions where the host tissue has an overly vigorous immune reaction and causes injury (E.g. Urticaria)

Autoimmune reactions where the self is mis-identified as the non-self (E.g. Grave's disease)

16

What are the 4 components of cells that are the principal targets for cell injury?

Cell membranes
Nucleus
Proteins
Mitochondria

17

How does chemical damage to a cell occur?

Give an example

Some chemicals will act by combining with a cellular component

E.g. Cyanide binds to mitochondrial cytochrome and blocks oxidative phosphorylation

18

What types of injury produce high levels of free radicals?

Chemical
Radiation
Ischaemia reperfusion
Cellular ageing
High O2 concentration

19

What are some of the effects of free radicals on cells?

Attack membrane lipids and cause lipid peroxidation

Damage proteins and nucleic acids

Mutagenic

20

What are the three free radicals of biological significance?

OH* - Most dangerous

O2- (superoxide)

H2O2

21

How are OH* free radicals formed?

Radiation can directly lyse water

Fenton and Haber-Weiss reactions produce OH* from H2O2 and O2- (Note: This is one reason to remove these ROS quickly, to prevent OH* being formed)

22

Briefly, how is the body protected against free radicals and why it important for this to exist?

The anti-oxidant system protects against free radicals

Imbalance in free radial production and scavenging leads to ROS build up and cell injury (This is oxidative stress)

23

What 3 elements is the anti-oxidant system comprised of?

Give a brief explanation of each

Enzymes:

- Superoxide dismutase (SOD) catalyses the O2- -----> H2O2 reaction (H2O2 is less toxic)

- Catalases and peroxidases complete the process of ROS removal (H2O2 -----> O2 + H2O

Free radical scavengers such as:
Vitamins A, C and E
Glutathione

In the extracellular matrix storage proteins (E.g. Transferrins and ceruloplasmin) sequester transitional metals (E.g. Copper and iron) which catalyse the formation of free radicals

24

What is the function of heat shock proteins?

When protein folding or denaturation they ensure they are refolded correctly

If not possible, the protein is destroyed

Heat shock response plays a role in maintaining viability of proteins and thus maximising cell survival

25

What are the three main changes seen in cells seen with cell injury?

Cytoplasmic changes:

-Reduced pink staining due to accumulation of water (reversible)

-Followed by increased pink staining due accumulation of denatured proteins and ribosomes that have detached from the RER (irreversible)

Nuclear changes:

- Chromatin clumped slightly (reversible)

- Pyknosis (shrinkage), Karryohexis (fragmentation) and karryolysis (dissolution) of the nucleus (irreversible)

Abnormal cellular accumulations

26

What reversible changes to injured cells can be seen with an electron microscope?

Give a brief reason for each

Swelling of both cell and organelles due to Na+/K+ pump failure

Blebs - (small area of detachment of the plasma membrane from cytoskeleton, appears as a small swelling)

Clumped Chromatin due to low pH

Ribosomes separation from RER due to failure of energy dependant process that keeps ribosomes attached.

27

What irreversible changes to injured cells can be seen with an electron microscope?

Further cell swelling

Nuclear changes (pyknosis, karryohexis, karryolysis)

Swelling or rupture of lysosymes

Membrane defects/damage

Appearance of myelin figures (which are damaged membranes)

Lysis of ER due to membrane defects

Amorphous densities

28

Define Oncosis

The spectrum of changes that occurs in injured cells prior to death

29

Define Necrosis

The morphological changes that follow cell death in living tissue, largely due to the progressive degradative action of enzymes on a lethally injured cell

30

Where is necrosis found?

What does it cause?

What kind of timescale does it occur on?
Give an example of this

Necrosis is found where there is damage to the cell membranes and lysosomal enzymes are released into the cytoplasm and digest the cell

As a result cell contents often leak out and inflammation is often seen, the ultrastructural changes are those seen in irreversible cell injury

Necrotic changes develop over a number of hours (E.g. after Myocardial infarction it takes 4-12 hours before microscopic changes are seen)