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MDIS2614 – Directed Learning

Session 3 – Cell Injury and death

① Discuss the mechanism of apoptosis (see session 5)

Mechanisms of apoptosis: (Underwood 6th ed. pg 61-62)

 Apoptosis is initiated by two broad pathways, the extrinsic pathways and the intrinsic pathways,
which converge upon a final common effector pathway characterised by the activation of proteases
and DNAses.
o The intrinsic pathway:
 The intrinsic pathway acts to integrate multiple external and internal stimuli,
leading to alterations in the relative levels of pro- and anti-apoptotic members of
the Bcl-2 family.
 Bcl-2 can inhibit many factors that can induce apoptosis.
 In contrast, Bax – another member of the same family – forms Bax-Bax dimers which
enhance apoptotic stimuli.
 Therefore, the ration of Bcl-2 to Bax determines the cell’s susceptibility to apoptotic
stimuli, and constitutes a ‘molecular switch’ which determines whether a cell will
survive, leading to tissue expansion, or undergo apoptosis.
 The intrinsic pathway responds to stimuli such as growth factors (inhibit apoptosis)
and biochemical stress (induces apoptosis).
 DNA damage represents a particular form of cell stress, which leads to
stabilisation of the protein product of the p53 gene.
 p53 is a multifunctional protein which induces cell cycle arrest and initiates
DNA damage repair.
 However, if this is unsuccessful, p53 can induce apoptosis via activation of
pro-apoptotic members of the Bcl-2 family.
o The extrinsic pathway
 The extrinsic pathway is a specific mechanism for the activation of apoptosis
characterised by ligand-binding at death receptors on the cell surface.
 Receptors include members of the tumour necrosis factor receptor (TNFR)
gene family, e.g. TNFR1 and Fas (CD95).
 Ligand binding at these receptors promotes clustering of receptor molecules on the
cell surface, and the initiation of a signal transduction cascade resulting in the
activation of caspases.
 This pathway is the mechanism by which the immune system eliminates
lymphocytes that would otherwise produce self-antigens.
 The execution phase
o Activation of apoptosis by either the intrinsic or extrinsic pathways results in a cascade of
activation of caspases.
o Triggering of apoptosis first leads to the activation of initiator caspase, which in turn cleaves
other pro-caspases to produce active executioner caspases which cause degradation of
many targets including the cytoskeletal framework and nuclear proteins.
o The nucleus shrinks (pyknosis) and fragments (karyorrhexis).
o The cell shrinks, retaining an intact plasma membrane, but alteration of this membrane
rapidly induces phagocytosis.
o Dead cells not phagocytosed fragment into smaller membrane-bound apoptotic bodies.
o There is no inflammatory reaction to apoptotic cells.
o Morphologically, apoptosis is recognised as death of scattered single cells which form
rounded, membrane-bound bodies; these are eventually phagocytosed and broken down by
adjacent unaffected cells.

② Why is apoptosis essential in nature?


th
(Underwood 6 ed. pg 61)

Apoptosis is essential in nature because it (alongside mitosis) ensures a continuous renewal of cells,
rendering a tissue more adaptable to environmental demands than one in which the cell population is static.

③ What are the mechanisms which cause cellular damage?

The specific mechanisms which cause cell damage and death are innumerable, but it seems that the
following are the most important: (Workbook pg 19-20)

1. Damage to the cellular membranes with subsequent functional abnormalities.


o This includes failure of the sodium pump.
2. Interference with protein synthesis.
3. Interference with energy production.
4. Changes to genetic behaviour.
o This can be caused by DNA which is incompatible with life or DNA which results in abnormal
cell growth.
④ What are the differences between:
(Workbook pg 20-21)

a. Degeneration and cell death?

Degeneration:
Reversible cell damage, often called degeneration, is a common phenomenon. If the cause of the
damage is removed, the cell will once again become normal. However, if the situation deteriorates,
the affected cells will die and become necrotic.

Cell death:
In contrast to degeneration, cell death is the condition where irreversible damage has led to the
inability of a cell to perform any useful function, and thus the cell will die.

b. Cell death and necrosis?

Cell death:
Cell death may be defined as the condition where irreversible damage has led to the inability of the
cell to fulfil any useful function.

Necrosis:
necrosis may be defined as the circumscribed death of a cell or group of cells within a living
organism with structural evidence of cell death.

c. Cell death/necrosis and apoptosis?

Necrosis:

Pathological cellular or tissue death in a living organism,


always due to pathological injury

Apoptosis:

A form of normal or pathological individual cell death


characterised by activation of endogenous
endonucleases. Induced wither by physiological or
pathological stimuli.
⑤ What are the mechanisms of the nuclear changes of necrosis?
th
(Underwood 6 ed. Pg 62)
The nucleus shrinks (pyknosis) and fragments (karyorrhexis) or it may be digested by enzymes and slowly
disappear (karyolysis).

⑥ Is necrosis “good” or “bad”? Motivate.

Good. It eliminates pathologically injured cells – it is a defence mechanism.

⑦ Is apoptosis “good” or “bad”? Motivate.

Good. It eliminates cells which have reached the end of their life span.

⑧ How does gangrene differ from necrosis?


(Workbook pg 22)

Gangrene is necrosis accompanied by putrefaction.

⑨ What is an infarct?

An infarct is a localised area of ischaemic necrosis. (Slides)

⑩ Why are some infarcts triangular and other irregular in shape?


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(Underwood 6 ed. pg 129)

The overall shape of infarcts depends upon the territory of perfusion of the occluded blood supply; some
classic appearances are the wedge-shaped infarcts seen in the lung and the triangular infarcts (conical in
three dimensions) seen in the kidneys at autopsy. Other scarred infarcts, such as those in the spleen, are less
predictable because the blood supply is less regular and marked overlaps of vascular territories occur, and
because the soft tissue distorts as the scar contracts. In the brain, the dead tissue is cleared away so
efficiently that a fluid-filled cyst is often all that remains

⑪ What is the effect of alcohol on liver cells?


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(Underwood 6 ed. Pg 364)
Binge drinking causes severe toxic injury to hepatocytes.

Chronic alcoholism causes either:

 Steatosis alone – reversible metabolic alteration in liver cells.


 Steatohepatitis – cell injury and death with progressive fibrous scarring leading to cirrhosis.
⑫ What is the effect of high dosages of paracetamol on liver cells?

Excessive dosages of paracetamol has a toxic effect on liver cells, it causes necrosis.

⑭ What are the morphological differences between enzymatic and traumatic fat necrosis? Why is
this so?