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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?



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?



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