Lecture 1: Cell injury, adaption and death Flashcards
What are the 4 main effects of injurous stimulus on cells
Reduced energy production, damage to cell membranes, increased intracellular ca2+ concentration and damage due to free radicals.
What are the 6 main causes of cell stress and injury
Physical, Chemical, Biological, Immunologic, Genetic derrangements and nutritional imbalances
What are the effects of reduced energy production/ available ATP have on the injured cell
Reduced energy available for
- repair enzymes to fix damage
- protein synthesis. Ribosomes also detach
- ATP driven membrane ion pumps- which leads to swelling due to increased Na+ and water entering cell as well as Ca2+ increase
What are some ways that ATP can be depleted during cell injury
hypoxia, damage to glycolytic enzyme or damage to mitochondria
What are some ways cell membranes are damaged in cell injury
Directly due to free radicals, following hypoxia, membrane targeting bacterial toxins, following failure of Ca2+ pump
What are the effects of damage to cell membranes on the injured cell
- Loss of cellular contents, therefore loss of osmotic balance
- damage to transmembrane ion pumps
- Autolysis due to injury of lysosomal membranes
- Formation of non selective high conductance channels in mitochondrial membrane- loss of oxidative phosphorylation
- decrease in content of membrane phospholipids due to activation of phospholipases
What are some ways intracellular Ca2+ concentration increases in cell injury
Reduced activity of the plasma membrane Ca2+ pump due to membrane damage/ reduced ATP
What are the effects of increase in intracellular Ca2+ concentration on the injured cell
Activates destructive Ca2+ enzymes like
- ATPases–> use up energy
- Phospholipases–>damage lipids
- Proteases–> break down proteins
- Endonucleases–> fragments DNA
What are the effects of damage due to free radicals on the injured cell
Free radicals
- initially cause autocatalytic reactions
- attack double bonds in unsaturated fatty acids in membranes,
- oxidise amino acid residue side chains in proteins
- reacting with thymine in nuclear and mitochondrial DNA
What are some ways free radicals can accumulate (oxidative stress)
Ionising irradiation, enzymatic metabolism of chemicals, drugs, oxygen toxicity and normal metabolism.
This happens when more free radical present than can be coped with by defense mechanisms
What are the other two sub effects of injurous stimulus on cells
Damage to proteins and Damage to nuclear or mitochondrial DNA
What initiates the cells response to most types of stress or damage?
Intracellular signalling molecules
- Heat shock transcription factors which induce expression of heat shock proteins; molecular chaperones that aid the repair of damaged proteins in the cell
- Stress kinases which initiation phosphorylation cascades which coordinates a cell’s response to damage
What does specific signalling protein : p53, BMF, Bim and Bad involved in/ what type of damage
p53: DNA damage -> apoptosis or halt to cell division if repairable
BMF: actin cytoskeleton damage
Bim: microtubule damage
Bad: cell stress due to inadequate stimulation by growth factors
What are the 3 adaptive responses to mild injurous agents (eg. chronic irritant) or stressors (eg. increased workload, mildly altered environmental conditions) and what do they mean
- Hypertrophy (increased size of individual cells) or Hyperplasia (increased number of cells)
- Atrophy (cell shrinkage)
- Metaplasia (reversibly changing from on cell type to another
What type of stress causes hypertrophy and hyperplasia and what activates these processes
When there increased functional demand, increased external stimulation= type of stress
Activated by stimulation of intracellular signalling pathways which activate cellular genes.
What are two ways hyperplasia is achieved
The cell in question can have increased cell division or the increased division of residing local stem cells or division of stem cells that emigrate into adapting tissue from bone marrow
What type of stress causes atrophy and what enables it to happen
Stress is reduced functional demands, reduced supply of nutrient or growth factors, reduced stimulation by nerves. Enabled by proteolytic systems like lysosome for autophagy and ubiquitin-proteosome pathway
What type of stress causes metaplasia and what activates this process
Stress is mild damage which can be better withstood by another type of cell.
Activated by growth factor signals and Extracellular matrix components in the cells environment which reprograms stem cells that reside in normal tissues. This makes them differentiate along a new pathway
What does irreversible cell injury lead to and when is the injury deemed irreversible
Leads to death. this is when the cell is unable to reverse membrane and mitochondrial dysfunction even after the injurious stimulus is removed
Compare the two ways a cell can die, and the main differences in what is required and what tends to result
Necrosis is passive form of cell death due to overwhelming damage whereas Apoptosis is programmed cell death and requires time and energy. Necrosis is always pathological and messy. It causes cytosolic contents to leak into extracellular space and induce inflammatory response. Apoptosis does not cause leak of cytosolic contents.
How does necrosis in a tissue appear, including affects to appearance of the nuclei
It affects large numbers of cells in a tissue. The cytoplasm is often featureless due to denaturation and autolysis .
The nuclei show fragmentation and fading of chromatin.. Sometimes prior to fragmentation, the chromatin can shrink into a dense mass at the margin of the nucleus. this is pyknosis.
What is the name for fragmentation of chromatin and what is the name for fading of chromatin
Frag: karyorrhexis
fading: karyolysis
What happens to necrotic cells a couple of days later
The cells and fragments are removed by phagocytic cells. If not promptly removed it can cause the precipitation of calcium called dystrophic calcification
When is apoptosis most common to occur after
DNA damage, stress due to inadequate GF supply, mild hypoxia or accumulation of damaged proteins
Why is apoptosis needed sometimes in non injured tissues (it role besides removing terminally injured cells)
It also removes unwanted cells in Embryogenesis, self reactive immune cells, neoplastically transformed cells, and virus infected cells
How does cell save energy for apoptosis and what mediates the events of apoptosis
Programmed destruction of cell machinery that uses a lot of energy to conserve it for apoptosis
Caspase enzyme cascade mediates apoptosis by activating each other by proteolytic cleavage which removes inhibitory domains.
How does the cell fall apart in apoptosis and what enzymes help to digest proteins
Chromatin is cleaved and condenses and membrane bound blebs containing cytosolic contents and organells break off the cell and are phagocytosed by neighbouring cells or immune cells.
Enzymes like executioner capsases digest cellular proteins and activate other enzymes (eg. nucleases to digest DNA)
