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What can severe changes in the environment of a cell lead to? (3)

Cell adaptation, injury or cell death


Degree of injury to cell following severe changes in environment depends on what? (3)

–Type of injury
–Severity of injury
–Type of tissue


How is the cell injury response part of a continuum?

Stimulus: Physiological --> Harmful

Response: Homeostasis --> Cellular Adaptation --> Cellular Injury --> Cell death


What kind of things can cause cell
injury? (7)

• Hypoxia
• Toxins
• Physical agents
• Radiation
• Micro-organisms
• Immune mechanisms
• Dietary insufficiency and deficiencies, dietary excess


Give examples of physical agents that can cause cell injury (4)

– Direct trauma
– Extremes of temperature
– Changes in pressure
– Electric currents


What is hypoxia?

Deficiency in the amount of oxygen reaching the tissues


Define cyanosis

A bluish discoloration of the skin due to poor circulation or inadequate oxygenation of the blood
- Caused by hypoxia.


What does frostbite most commonly affect?

Fingers, nose, toes


What can frostbite often result in?



What is cellulitis?

Inflammation of skin (subcutaneous connective tissue)


How can the worsening/improving of cellulitis be tracked?

Draw around affected area


What is the difference between hypoxia and ischaemia? Which is considered worse and why?

Hypoxia: Decreased oxygen supply
Ischaemia: Decreased blood supply

- Ischaemia deprives the cell of of oxygen but also many other things (e.g. sugars) that could impact metabolic processes.


What are the four main causes of hypoxia?

– Hypoxaemic hypoxia – arterial content of oxygen is low
• Reduced inspired p02
at altitude
• Reduced absorption secondary to lung disease

– Anaemic hypoxia – decreased ability of haemoglobin to carry oxygen
• Anaemia
• Carbon monoxide poisoning

– Ischaemic hypoxia - interruption to blood supply
• Blockage of a vessel
• Heart failure

– Histiocytic hypoxia – inability to utilise oxygen in cells due to disabled
oxidative phosphorylation enzymes
• Cyanide poisoning


Difference in sensitivity to hypoxia: brain vs skin

Neurones = few minutes
Fibroblasts = few hours


What is urticaria?



How does the immune system damage the
body’s cells? (2)

• Hypersensitivity reactions - host tissue is
injured secondary to an overly vigorous
immune reaction, e.g. urticaria (= hives)
• Autoimmune reactions - immune system fails
to distinguish self from non-self e.g. Grave’s
disease of thyroid.


Which cell components are most
susceptible to injury? (4)

- Membranes
- Nucleus
- Proteins
- Mitochondria


Why do calcium and iron levels need to be controlled very carefully in the body?

They are very metabolically active (catalyse reactions).


What is happening at a molecular level in hypoxia? Reversible injury.

- Stop blood supply to group of cells.
- Mitochondria will use up the supplies they have.
- Oxidative phosphorylation slowly dwindles.

- Decreased production of ATP.

- Sodium pumps are dependant on ATP --> will grind to a halt.
- Sodium rushes into the cell followed by water and calcium (Ca also from ER and mitochondria) and there is a potassium efflux --> cellular swelling, loss of microvili, blebs, ER swelling, myelin figures.
- Revert to anaerobic respiration (glycolysis) which causes a drop in glycogen and the cells pH --> latter leads to clumping of chromatin.

- Ribosomes are kept at the ER using energy, without ATP, they are dislocated, proteins cannot be made --> in hepatic cells this means that apolipoproteins cannot be made and lipids can't be metabolised --> lipid deposition in liver cells --> fatty liver (this end result in the liver can also be a consequence of alcohol abuse)


What is happening at a molecular level in prolonged hypoxia? Irreversible injury.

- Difficult to say why but likely to be due to the high influx of calcium into the cell (from extracellular, mitochondria and ER).

Calcium activates many enzymes:
- ATPase: Decreased ATP
- Phopholipase: Decreased phospholipids (attacks membranes)
- Proteases: Disruption of me membrane and cytoskeleton proteins (skeleton of cell starts to break down and it changes shape)
- Increases activity of endonuclease: Nuclear chromatin damage (breaks down DNA)


Why can different insults result in the same damage?

Sequence of events for other insults may be different
but as the cell has a limited responses to injury,
outcome often similar.


Two types of injury that damage membranes primarily

- Extreme cold (e.g. frostbite)
- Free radicals


- What is a free radical?
- What else is it often to referred to as?
- Comment on its reactivity.

- Single unpaired electron in an outer orbit
- Reactive oxygen species
- High reactivity: an unstable configuration hence react with other molecules, often producing further free radicals


What are the three free radicals that are of particular biological significance in cells?

- OH• (hydroxyl): the most dangerous
- O2- (superoxide)
- H2O2 (hydrogen peroxide)


How are free radicals produced?

- (Need free radicals to stay alive) Normal metabolic reactions: e.g. oxidative phosphorylation.

- Inflammation: oxidative burst of neutrophils (used as part of phagocytosis).

- Radiation, H20 -> OH radical (dangerous).

- Contact with unbound metals within the body: iron
(by Fenton reaction) and copper.

- Drugs and chemicals: e.g., in the liver during
metabolism of paracetamol or carbon tetrachloride
by P450 system.


Where are free radicals made from oxidative phosphorylation stored and why?

Stored away in mitochondria --> avoid damage.


What is the damage in haemachromatosis caused by?

Damage caused by the high amounts of free radicals produced by the excess of iron.


What is the damage in Wilson's disease caused by?

Damage caused by the high amounts of free radicals produced by the excess of copper.


How does the body control free radicals?

- Anti-oxidant system: donate electrons to the
free radical – vitamins A, C and E (ACE System).

- Metal carrier and storage proteins sequester iron and copper (transferrin for iron and ceruloplasmin for copper).

- Enzymes that neutralise free radicals.


Name three enzymes that neutralise free radicals

– Superoxide dismutase
– Catalase
– Glutathione peroxidase


What is oxidative imbalance?

If the number of free radicals overwhelms the anti-oxidant system. Leads to injury of cells by free radicals.


How do free radicals injure cells?

Most important target are lipids in cell membranes.
– Cause lipid peroxidation. – This leads to generation of further free radicals → autocatalytic chain reaction.

• Also oxidise proteins, carbohydrates and DNA
– These molecules become bent out of shape, broken or cross-linked
- Mutagenic DNA - protein can't be transcribed or may be a carcinogenic mutation.


What is lipid peroxidation?

Radical takes an electron from an atom in the lipid membrane which then takes an electron from its neighbouring atom -> chain reaction down the membrane -> membrane disruption that can lead to cell death.


Describe a protection system against free radicals found in all living organisms.

- Heat shock proteins
• In cell injury heat shock response aims to ‘mend’
mis-folded proteins and maintain cell viability.


What are heat shock proteins?

- Lab: increased cells environmental temperature.
- Cells stopped producing all their normal proteins and instead produced this group of proteins: heat shock proteins.
- These proteins however are produced in response to any njury to the cell.


What are heat shock proteins also known as?

Unfoldases or chaperonins.


Give an example of a heat shock protein.



Changes to cell appearance in hypoxia (3)

• Cytoplasmic changes.
• Nuclear changes.
• Abnormal cellular accumulations (e.g fat in hepatocytes).


Appearance of injured cell under light microscope.

Injured: Appear pale and swollen because membranes disrupted and sodium and water are able to rush into the cell.


Appearance of dead cell under light microscope (4)

- Eosinophylic cytoplasms (pink, deeply stained) because proteins have denatured/coagulated.

- Pyknosis: nucleus shrinks and becomes very dark, irreversible condensation of chromatin.

- Karyorrhexis: less common, nucleus breaks into smaller fragments.

- Karyolysis: dissolution of cell nucleus.


Appearance of a cell undergoing reversible injury from hypoxia under an electron microscope. (8)

- Generalised swelling
- Blebs: cytoskeleton being broken down by proteases activated by calcium leading to loss of shape
- Lysosomal membrane subject to leakiness
- Autophagy by lysosomes
- Clumping of nuclear chromatin
- ER swelling
- Dispersion of ribosomes
- Mitochondrial swelling


Appearance of a cell undergoing irreversible injury from hypoxia under an electron microscope. (6)

- Rupture of lysosomes and autolysis
- Nucleus: pyknosis, karyolysis or karyorrhexis
- Defects in cell membrane (visible holes)
- Myelin figures (disrupted cell membrane/lipid fixation)
- Lysis of ER
- Mitochondrial swelling


How to tell apart an injured cell from a dead cell?

- Test for function rather than appearance.
- Dye exclusion test: any cells with dye in them at the end are considered to be dead.


Define oncosis

Oncosis: cell death with swelling, the spectrum of
changes that occur in injured cells prior to death.


Define necrosis

Necrosis: in a living organism the morphologic
changes that occur after a cell has been dead some
- Seen after 12-24 hours.


What are the two main types of necrosis?
Name two other special types.

- Coagulative
- Liquefactive (colliquitive)

Two other special types:
– Caseous
– Fat necrosis


What causes coagulative necrosis and where is it mostly found?

- Protein desaturation: build up of protein matter in cell.
- In solid organs (lot of connective tissue support).


What causes liquefactive necrosis and where is it mostly found?

- Enzyme release (e.g from lysosomes)
- In loose tissue and in infected regions with many neutrophils.


What does coagulative necrosis look like?

- Cellular architecture is somewhat preserved, “ghost outline” of cells.
- Neutrophils may be present but not in vast numbers therefore not characteristic of an abscess/infection.
- May display karyolysis.


What does liquefactive necrosis look like?

- Enzyme degradation is substantially greater than denaturation. Leads to enzymatic digestion (liquefaction) of tissues.
- Lack of any distinct characteristics.
- May be able to see some neutrophils.
- Results in inflammation of surrounding tissue.


What is caseous necrosis?

•Contains amorphous (structureless) debris. (c.f. ghost outline in coagulative necrosis).
•Particularly associated with infections, especially tuberculosis (and granulomatous inflammation).


What does caseous necrosis look like?

- White splodges (looks like cheese).

- Under microscope: structure-less debri with some inflammatory cells present.


What is fat necrosis often secondary to? Why?


- Enzymes from pancreas can leak out into the abdominal cavity.
- They attack the lipids within the abdominal cavity.
- Fatty acids produced from the breakdown of triglycerides react with calcium and form calcium soaps.


What is a sign of fat necrosis in breast tissue?

Formation of a hard lump.


Define gangrene

Necrosis visible to the naked eye (appearance of necrosis)


Define infarction

Infarction is necrosis caused by reduction in arterial blood flow.
– A cause of necrosis.
– Can result in gangrene.


Define infarction

An area of necrotic tissue which is the result
of loss of arterial blood supply (an area ischaemic necrosis).


What is dry gangrene?

Necrosis modified by exposure to air (coagulative necrosis).


What is wet gangrene?

Necrosis modified by infection (liquefactive necrosis).


What is gas gangrene?

Wet gangrene where the infection is with anaerobic
bacteria that produce gas.


Why can gas gangrene be fatal?

Bacteria can spread very rapidly fro neurotic tissue to surrounding blood vessels and therefore highly dangerous .


Why is gas gangrene a risk in dirt road accidents.

Anaerobic bacteria are usually in the soil.
Accident -> rupture in skin allowing entrance point to anaerobic bacteria -> can result in gas gangrene.


What are the commonest causes of infarction?

Thrombosis and embolism.


What is the difference between a blood clot and a thrombus?

Blood clot occurs following damage, e.g a cut.
Thrombus is pathological and occurs in an otherwise intact vessel.


What colour is an infarction in the heart?

May appear red if it is old.


What is an embolus?

An embolus is anything that travels through the blood vessels until it reaches a vessel that is too small to let it pass.


How can tissue become infarcts? (3)

- Thrombus
- Embolus
- Application of external pressure (e.g in hernia, sigmoid volvulus and testicular torsion)


What is testicular torsion?

Testicular torsion occurs when the spermatic cord (from which the testicle is suspended) twists, cutting off the testicle's blood supply, resulting in ischaemia and a necrotic testicle. The principal symptom is rapid onset of testicular pain.


What is sigmoid volvulus?

Sigmoid twists around on itself, cutting off its own blood supply becoming necrotic and gangrenous.
Can also appear hugely dilated because gas produced by bacteria in that part of the gut can't get out.


_______ _______ = Infarct

Ischaemic Necrosis


Example of where coagulative necrosis would occur.

Myocardial Infarct.


Example of where liquefactive necrosis would occur.

Cerebral Infarct.


Why are some infarcts white? What shape do they tend to appear as?

• ‘Solid organs’, occlusion of an end artery = no blood supply = white
• Often wedge-shaped
• Coagulative necrosis

(Solid organ: heart, spleen, kidney, etc)


Why are some infarcts red? (6)

Have bled into the tissue; infarcts accompanied by haemorrhage. This can be due to a number of reasons:

- Loose tissue
- Dual blood supply (Blood can leak out (due to the surrounding inflammation) of vessels that are still being supplied. Supply to other vessels not enough to rescue the lung, however.)
- Numerous anastomoses (Bowels have collateral blood supply. Allow vascular bypass. Not enough to rescue organ but does cause haemorrhage.)
- Prior congestion (Full of a lot of blood before it becomes infarcts
E.G heart failure or problems with venous return)
- Raised venous pressure
- Re-perfusion


What is the consequence of infarction and what does this depend on?

- Can remain completely oblivious to it
(People that have had operations or have had malignancies --> can have many small pulmonary emboli causing infractions)
- Infractions can however often cause death

Depends on:
– Alternative blood supply
– Oxygen content of the blood (E.G Start off anemic --> area of infarction will be much worse)
– Tissue involved
– *Speed of ischaemia

*Slowly reduce blood supply:
Cells will begin to adapt
Other blood supplies will be made available to that area


What is ischaemia-reperfusion injury?

If blood flow is returned to a damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow hadn’t been returned.


Possible causes ischaemia-reperfusion injury? (3)

– Increased production of oxygen free radicals with
– Increased number of neutrophils resulting in more inflammation and increased tissue injury.
– Delivery of complement proteins and activation of the complement pathway.


Necrosis and oncosis cause membranes to become leaky, what local and systemic effects can this lead to?

- Things in high concentration inside the cell leak out.

– Can cause local inflammation (Inflammation tends to be characteristic of necrosis, often used as a landmark of sorts)
– May have general toxic effects on body
– May appear in high concentrations in blood and can aid in diagnosis


How can a leaky membrane aid in diagnosis in the case of necrosis?

- Specific enzymes or proteins leak out
- Can alert us of damage
- Inform which tissue the damage is in
- Provide idea of how bad damage is


Name three clinically important things that can leak out cells in necrotic tissue.

- Potassium
- Enzymes
- Myoglobin


3 instances in which potassium can leak out of cells and the consequence of this.

- K+ in high concentration inside the cell
- Leaks out if membrane damaged

- K+ used to hold heart still in surgery

- Massive area of myocardial infarction = a lot of K+ released in close proximity to the heart, it can stop the heart
- Areas of severe burns: break down of many cells quickly, release of K+, can have cardiac arrest secondary to burns
- Tumour lysis syndrome: severe chemotherapy leading to many cancer cells being destroyed at the same time, releasing a lot of K+, has cardiac effects


How can you differentiate between an angina and a myocardial infarction by testing bloods?

Can differentiate angina (no cell death) from myocardial infection (cell death has occurred) by whether or not you get raised levels of enzymes/proteins in the blood that are specific to the heart.

Used to use AST then CK and now troponin (particular it troponin I).


Damage to what causes leakage of myoglobin?

- Damage to skeletal muscles
- Known as rabdomyolysis
- Can be a result of acid trauma or following intense excercise (in a hot climate with insufficient hydration)


What problems does leakage of myoglobin from damaged cells cause?

- Myoglobin blocks glomeruli in the kidney and causes renal failure.
- Myoglobin presents in urine in large quantities; urine appear brown.


Define apoptosis

- Cell death with shrinkage, induced by a
regulated intracellular program where a cell
activates enzymes that degrade its own nuclear DNA
and proteins.
- Occurs within a couple of hours.
- Characteristic microscopic appearance.


Describe DNA breakdown in apoptosis

Characteristic DNA breakdown
• Non-random, internucleosomal cleavage of DNA
(- In oncosis, DNA is chopped into pieces of random length)



• Equal and opposite force to ________
• Active process
• ________ activated that degrade nuclear DNA and protein
• ________ integrity is maintained = no ________
• ________ enzymes not involved
• Quick, cells gone in a few ________
• Pathological or ________

• Equal and opposite force to mitosis
• Active process
• Enzymes activated that degrade nuclear DNA and protein
• Membrane integrity is maintained = no inflammation
• Lysosomal enzymes not involved
• Quick, cells gone in a few hours
• Pathological or physiological (all necrosis is pathological)


When does apoptosis occur physiologically?

- Maintain steady state: New cells will come in by mitosis and old cells that are redundant will be removed by apoptosis

- Hormone-controlled involution (E.G ovaries as oestrogen decreases with age)

- Embryogenesis
E.G cells between digits become apoptotic


When does apoptosis occur pathologically?

• Cytotoxic T cell killing of virus-infected or neoplastic cells (tumor cells)

• When cells are damaged, particularly with damaged DNA

• Graft versus host disease


What is graft versus host disease?

Seen in patients who have had a bone marrow transplant for cancers such as leukaemia
Patients WBC's are cancerous
Strong doses of radio/chemotherapy given to rid of all bone marrow cells that develop into WBCs
Donated bone marrow cells given through drip --> travel to bone marrow and develop into new WBC's
Problem: sometimes these WBC's start to recognise the host as foreign
Results in graft versus host disease
Skin and bowel cells are particularly sensitive to this


What are the three phases apoptosis?

• Initiation
• Execution
• Degradation & phagocytosis


Define karyorrhexis

It is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm.


What does apoptosis look like?

- Cell Shrinkage
- Condensation of proteins within the cells
- Chromatin within the nucleus is broken down into regular sized chunks and clumps into parts of the inner nuclear membrane
- ^ is a form of karyorrhexis (sometimes seen in necrosis but typically characteristic of apoptosis)
- Cell then begins to fragment up into apoptosis bodies
- Apoptotic bodies: buds containing bits of nucleus, mitochondria and other cellular organelles


What is the difference between blebbing and budding?

Blebbing occurs in oncosis whereas budding occurs in apoptosis


Which group of enzymes act as the effector enzymes in the process of apoptosis?



What are the initiation and execution stages of apoptosis triggered by?

- Triggered by two mechanisms – intrinsic and extrinsic
- Both result in activation of caspases


Describe the role of caspases

– Enzymes that control and mediate apoptosis
– Cause cleavage of DNA and proteins of the


Where does the initiating signal come from for the intrinsic pathway?

Inside the cell


What triggers the intrinsic pathway? (2)

– Most commonly irreparable DNA damage
– Withdrawal of growth factors or hormones


How are caspases activated?

• p53 protein is activated and this results in the outer mitochondrial membrane becoming leaky

• Cytochrome C is released from the mitochondria and this causes activation of caspases


Extrinsic pathway is initiated by _____ signals.



What triggers the extrinsic pathway?

- Cells that are a danger, e.g. tumour cells, virus-infected cells

- Detected by immune system by recognising molecules on the surface of the cell in danger


What is TNFα and what does it do?

- Tumor necrosis factor alpha - primarily produced by macrophages as an immunological response .

- Acts as one of the signals for apoptosis

– Secreted by T killer cells
– Binds to cell membrane
receptor (‘death receptor’) – Results in activation of


How does the body know that apoptotic bodies are to be phagocytosed?

- Membrane changes from cell --> apoptotic body
- Apoptotic bodies express proteins on their surface
- They can now be recognised by phagocytes or
neighbouring cells as something that needs to removed from the body
- Finally degradation takes place within the


Compare apoptosis against necrosis (8)

A vs N

- Shrinkage vs Swelling
- DNA breaks into equal fragments (controlled) vs Uncontrolled/random breakdown
- Budding vs Blebbing
- Membrane intact vs Disrupted membrane, early lysis
- Cellular contents: intact, released in Apoptotic bodies vs Enzymatic digestion, leak out of cell and release of proteome tic enzymes
- Single cells affected vs Contiguous groups of cells
- Nucleus: fragmentation into nucleosome size fragments; form clumps beneath nuclear membrane vs Pykanosis/Kayorrhexis/Karyolysis
- No adjacent inflammation vs Frequent adjacent inflammation


How do the roles of apoptosis and necrosis/oncosis differ?

Oncosis/Necrosis: Invariably pathological role

Apoptosis: Often physiological, means of removing undated cells; may be pathological after some forms of cell injury especially DNA damage


What happens to something the cell can't metabolise?

Remains and accumulates within the cell


Where do abnormal cellular accumulations derive from?

– Cell’s own metabolism
– The extracellular space, e.g., spilled blood
– The outer environment, e.g. dust


What are the five main groups of intracellular

– Water and electrolytes
– Lipids
– Carbohydrates
– Proteins
– ‘Pigments’


What is hydropic swelling?

Swelling due to fluid accumulation in cells


What causes fluid accumulation in cells and what does this indicate?

- Occurs when energy supplies are
cut off, e.g. hypoxia
- Na+ and water flood into cell

- Indicates severe cellular distress


Which organ is fluid accumulation particularly a problem for? Why?

Because sits within the skull which has no give
Can cause damage to vital structures in brain and signal cord due to compression
Blood supply to brain compromised due to increased inter cranial pressure
Cerebral oedema - often cause of death following prolonged ischaemia or physical trauma


What is steatosis? Where is it often seen and why? How does mild steatosis present itself?

Steatosis: accumulation of triglycerides

Often seen in liver because it' stress major organ of fat metabolism

- Asymptomatic


What are the causes of steatosis? (4)

– Alcohol (reversible in about 10 days)
– Diabetes mellitus
– Obesity
– Toxins (e.g. carbon tetrachloride which is metabolised by the p450 system and produces free radicals)


How does a liver with steatosis appear?
(A) to the naked eye
(B) under a microscope

- Yellow
- Heavy
- Enlarged (cells swollen due to the fat accumulation)

- Droplets of fat
- Hepatocytes nucleus pushed to edge by fat