3. Cell Injury And Death Flashcards
What is involved in the maintenance of cellular steady state?
- preservation of genetic integrity
- normal enzyme content
- intact membranes and transmembrane proteins
- adequate supply of substrates and oxygen
What happens when cellular steady state is not maintained?
Cell injury.
Biochemical and/or morphological changes that occur when the steady state is perturbed by adverse influences
What happens when normal cell homeostasis is disrupted?
The cell either adapts or becomes injured. Cell injury can be mild and transient and therefore reversible, or it can be severe and progressive and therefore irreversible
What does irreversible cell injury lead to?
Cell death
Either necrosis or apoptosis
Name three types of cellular adaptation
- increased cellular activity (hyperplasia, hypertrophy)
- decreased cellular activity (atrophy)
- change in cell morphology (metaplasia)
Define hypertrophy
Individual cells increase in size (since the cells cannot divide)
Eg. Size and thickness of left ventricle increase due to systemic hypertension etc, muscle gets bigger
Define hyperplasia
The cell number increases, cells divide
Define atrophy
Cells shrink in size or number due to decreased demand
What effect do steroids have on the body in terms of cellular adaptations?
When used for a long time, steroids cause the adrenal glands to become atrophic - this then creates a problem if the steroids are stopped suddenly, it is recoverable if you reduce steroids slowly
Explain metaplasia
When cells change their shape and morphology in response to a change in stimulus - change function
Can be physiological or pathological
Physiological example = cervix goes through change from columnar to squamous epithelium
Give a physiological and pathological example of atrophy
Physiological = organ formation in embryology
Pathological = loss of innervation leading to muscle atrophy
Give a physiological and pathological example of hypertrophy
Physiological = skeletal and heart muscle in athletes
Pathological = left ventricular hypertrophy in response to systemic hypertension
Give a physiological and pathological example of hyperplasia
Physiological = increase in bone marrow cells producing red blood cells at high altitude
Pathological = angiogenesis in wound repair
Give an example of metaplasia
Barrett’s oesophagus = replacement of normal squamous epithelium with columnar glandular epithelium due to gastric acid reflux
Define hypoxia and anoxia
Hypoxia = reduction of oxygen to delivered to cells, often cause by ischaemia
Anoxia = complete loss of oxygen to cells
Define ischaemia
Lack of blood flow. Therefore a common cause of tissue hypoxia
Other than ischaemia, how else might tissue hypoxia arise?
There might not be enough oxygen in the blood to start off with, or the cells might not be able to use the oxygen (eg. Cyanide poisoning)
Explain reoxygenation
Reperfusion - generation of oxygen free radicals.
If an artery becomes infarct, and then the infarct artery becomes patent again (eg. In thrombolysis) some of the myocardium will be reperfused, this creates free radicals which can cause cell death.
So reperfusion is helpful but can also cause problems
How might a bullet shot affect tissues?
Tear small blood vessels over a large area leading to widespread devascularisation and subsequent ischaemic tissue death
The cavity also contains a vacuum and so dirt is sucked into the wound leading to infection
How does mechanical trauma cause cell injury?
Disrupts cell structure
Damages to walls of blood vessels leading to thrombosis and secondary ischaemic damage
Define hyperprexia
A fever with extreme elevation of body temperature greater than or equal to 41.5 degrees celcius
(Extreme temperature damage can be both internal or external)
Give examples of chemical agents that can cause cell injury
- alcohol
- tobacco smoke
- drugs
- poisons
- environmental
- occupational
What is the mode of action of chemical agents in terms of cell injury?
Different modes of action
Range from simple denaturation and breakdown of macromolecules (eg. Strong acids and alkalis)
To more subtle interferences will cellular metabolism (eg. Paracetamol poisoning)
Describe liver cirrhosis in terms of cell injury
Alcohol abuse causing long term cell injury and death, the liver tries to regenerate in a suboptimal way
What are the carcinogenic effects of asbestos?
Causes cancer of the bronchi and pleura.
Often happens 20 to 30 years after the exposure
Can also affect those living with the exposed person (on their clothes etc)
What are the two types of bacterial toxin?
Exotoxin = secreted from living bacterial cell eg. Pseudomembranous colitis
Endotoxin = secreted from the dead bacterium eg. E. coli
How do X-rays cause cell injury?
Generation of free radicals and direct damage to macromolecules
Free radicals are very reactive and cause bonds to form where they shouldn’t, causing damage
Which organs are most sensitive to ionising radiation?
Those with a high turnover rate (high proliferation rate)
Eg. Bone marrow, gonads, intestines
Which organs are not as sensitive to ionising radiation?
Uterus
Pancreas
Adrenal glands
How does UV light cause cell injury?
Can induce an inflammatory response several hours after exposure
Eg. Sunburn
How is ionising radiation used to our benefit?
To treat many cancers (radiotherapy) - used to produce cell injury on purpose
What are the targets of cell injury?
- mitochondrial function
- membrane integrity and function
- protein synthesis
- cytoskeleton
- genetic apparatus
What effect does mitochondria damage have?
Diminished oxidative phosphorylation and therefore reduced ATP levels. This leads to many more knock on effects
What effect does reduced ATP levels have on the sodium pump?
Plasma membrane ATP-driven sodium pump is reduced. Leading to consequent influx of sodium and calcium. This leads to isosmotic gain of water and acute cellular swelling
What effect does reduced ATP have on the pH of the cell?
Anaerobic glycolysis increases to generate ATP from glycogen. This depletes glycogen stores and results in accumulation of lactic acid. This lowers the intracellular pH
How does damage to mitochondria and therefore reduced ATP affect protein synthesis?
Decreased ATP and pH levels causes ribosomes to detach from rough endoplasmic reticulum and therefore reduces protein synthesis. Decreased protein synthesis leads to lipid deposition
Is cell injury caused by damage to mitochondria reversible or irreversible?
Potentially reversible. Restoration of blood flow allows the cell to recover normal function
What type of cell injury is cellular swelling/acute cellular oedema usually associated with?
Mitochondria injury due to hypoxia.
But may also occur with fever or damage due to toxins
What effect does alcohol have on the liver in terms of histology?
Acute = cell swelling Chronic = fat accumulation = steatosis (fatty liver, longstanding sublethal cell injury)
What is a free radical?
Highly reactive ions or molecules with single unpaired electron in outer orbital eg. oxygen free radicals
What is the free radical cascade effect?
Free radical injury generates more free radicals.
Chain reaction with molecules in membranes to produce additional free radicals
How do free radicals cause cell injury?
Damages proteins and nucleic acids - apoptosis.
What is superoxide and what does it do?
It is a free radical.
Bacterial killing by neutrophils and macrophages depends on formation of superoxide
Detoxification by superoxide dismutase and antioxidants e.g. vitamins A, C and E
What can cause damage to membranes?
- bacterial toxins
- viral proteins
- complement
- cytolytic lymphocytes
- various physical and chemical agents
What is the main cause of damage due to loss of membrane barriers?
Breakdown in metabolite gradients (leading to increased Ca2+)
What effect does increased Ca2+ have on enzymes?
It activates a number of enzymes (ATPases, phospholipases, proteases, endonucleases) with potential deleterious cellular effects.
Increased Ca2+ activates a number of enzymes. What are they and what deleterious effects do they have?
- ATPases (hastening ATP depletion)
- phospholipases (which cause membrane damage)
- proteases (break down membrane and cytoskeletal proteins)
- endonucleases (responsible for DNA fragmentation)
Other than enzymes, what else does Ca2+ levels have an effect on?
Muscle contraction
When does cell death occur?
When cells are unable to achieve a new steady state following environmental insults
What happens when there is irreversible breakdown of energy-dependent organised interactions between DNA, membranes and enzymes?
Cell death
Is cell death physiological or pathological?
Can be either. Not necessarily abnormal, epithelial surfaces constantly renew etc.
What are the two types of cell death?
- necrosis (passive, unprogrammed)
- apoptosis (active, programmed)
What is necrosis?
Cell death as a result of lethal cell injury
Passive (no need for energy)
Incites an inflammatory reaction (tissues die and release small effector molecules that drag in inflammatory reaction)
There are several distinct morphological types
What are the different types of necrosis?
- coagulative (most common, occurs in most types of solid tissues)
- caseous (TB, like cottage cheese, necrotic tissue loses all structure)
- colliquative (brain, tissue liquefies)
- gangrene (wet and dry, red cells break down, tissue becomes black/green, wet gangrene cannot dry out and becomes infected)
- fat, fibrinoid (fat becomes necrotic when traumatised, eg. seat belt injury)
Describe coagulative necrosis
- denaturation of intracytoplasmic protein
- dead tissue becomes firm and slightly swollen
- tissue shows retention of microscopic architecture
- type of ischaemic injury (except in brain)
- cellular proteins may leak into blood
Cellular proteins may leak into the blood in coagulative necrosis. How is this useful?
Can be diagnostically useful. Blood tests used to diagnose myocardial infarction.
What are the characteristics of coagulative necrosis?
Where the area has died it will be
- pale
- firm
- slightly swollen
What type of necrosis occurs in the brain?
Colliquative necrosis, as it does not have a collagenous tissue framework.
Necrotic neural tissue is liable to total liquefaction and the site is eventually marked by a cyst.
What type of necrosis is characteristic of tuberculosis?
Caseous necrosis.
- cheese-like
- cellular detail destroyed in this area, which is surrounded by granulomatous inflammation
- dead tissue lacks any structure
What type of necrosis is bowel infarct prone to?
Wet gangrene
What type of necrosis is seen in diabetes?
Dry gangrene (foot)
What is apoptosis?
Programmed cell death
Active, requires energy
What are physiological examples of apoptosis?
- embryogenesis
- involution
- elimination of self-reacting lymphocytes
What is involution?
The shrinkage of an organ in old age or when inactive eg. the womb after childbirth
What are pathological examples of apoptosis?
- DNA/protein damage
- viral infections
- cell killing by cytotoxic T-cells
- chemo/radiotherapy
What are the effector molecules of apoptosis?
capsases
What activates capsases (effector molecules of apoptosis)?
Apoptosis initiating factor (AIF) and cytochrome C
when released into the cytosol, they are normally stored away in mitochondria
What is p53?
The ‘guardian of the genome’
Activated by DNA damage and causes the elimination of damaged cells by apoptosis
What does a mutation in p53 cause?
They are very common in malignant tumours.
Thus allowing cells to accumulate genetic abnormalities and become malignant
What does Bcl-2 do?
It sequesters cytochrome C and therefore inhibits apoptosis
Describe another way in which tumours gain the ability to proliferate in an uncontrolled way
Activating mutations that lead to bcl-2 over-expression and therefore the inhibition of apoptosis
Is the pathway for apoptosis extrinsic or intrinsic?
There is both an extrinsic or intrinsic pathway
Main features of necrosis
Multiple cells, enlarged cell size, invariably pathologic (irreversible cell injury), frequent adjacent inflammation
Main features of apoptosis
Single cell, reduced cell size, often physiologic (means of eliminating unwanted cells), no adjacent inflammation
Is the plasma membrane disrupted or intact in necrosis and apoptosis?
Necrosis = disrupted plasma membrane
Apoptosis = intact plasma membrane
Describe the nucleus in the process of necrosis
Pyknosis - karyorrhexis - karyolysis
Describe the nucleus in the process of apoptosis
fragmentation - apoptotic bodies
Describe the cellular contents during necrosis and apoptosis
Necrosis = enzymatic digestion, may leak out of cell
Apoptosis = intact, may be released in apoptotic bodies
