Flashcards in MoD S1+2 - Cell Injury Deck (78)
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
What are the major causes of cell injury?
Chemical agents and drugs
Dietary insufficiency or excess
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
What are the 4 major types of hypoxia?
Give a brief description and example of each
Arterial pO2 is low E.g. Reduced inspired PO2 at altitude
Decreased ability for haemoglobin to carry O2 E.g. anaemia, CO poisoning
Interruption to blood supply E.g. Vessel blockage
Histiocytic: Inability to utilise O2 in cells due to disabled oxidative phosphorylation E.g. Cyanide poisoning
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
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
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
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
When does cell injury progress from reversible to irreversible?
Not really known/not well understood
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
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
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
Give examples of physical agents that may cause cell damage
Sudden change in atmospheric pressure
Give examples of chemical agents and drugs that might cause cell damage
Glucose or salt in hypertonic solutions
O2 at high concentrations
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)
What are the 4 components of cells that are the principal targets for cell injury?
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
What types of injury produce high levels of free radicals?
High O2 concentration
What are some of the effects of free radicals on cells?
Attack membrane lipids and cause lipid peroxidation
Damage proteins and nucleic acids
What are the three free radicals of biological significance?
OH* - Most dangerous
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)
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)
What 3 elements is the anti-oxidant system comprised of?
Give a brief explanation of each
- 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
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
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
What are the three main changes seen in cells seen with cell injury?
-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)
- Chromatin clumped slightly (reversible)
- Pyknosis (shrinkage), Karryohexis (fragmentation) and karryolysis (dissolution) of the nucleus (irreversible)
Abnormal cellular accumulations
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.
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
Appearance of myelin figures (which are damaged membranes)
Lysis of ER due to membrane defects
The spectrum of changes that occurs in injured cells prior to death
The morphological changes that follow cell death in living tissue, largely due to the progressive degradative action of enzymes on a lethally injured cell