1.2 - Cell Injury + Cell Death

Question 1

What is cell injury

Answer 1

• cells have effective mechanisms to deal with mild environmental changes
• more severe changes lead to cell adaptation, injury or cell death
• injured cell will either adapt, revert back to normal or lead to cell death
• degree of injury depends on type, severity, duration of injury and the type of tissue

Question 2

Example of cell response to injury – heart

Answer 2

initial insult = myocytes having to work harder
adaptation = cardiac myocyte hypertrophy
continued insult and adaption = ventricular hypertrophy
continuing insult = myocytes require more oxygen (as they are bigger)
second insult = hypoxia
irreversible cell injury + death = myocardial infarction / arrythmia

*there are many treatments that would help at different stages of this path, eg valve replacement, heart failure medications (to increase O2 delivery to the heart), stents, bypass, anti-arrythmics, ICDs etc)

Question 3

Causes of cell injury – environmental and non-environmental (details on separate cards)

Answer 3

environment
- hypoxia
- toxins + poisions
- immune mediated
- physical agents
- infection
- nutrition + dietary

non-environmental
- genetic
- aging

Question 4

Causes of cell injury: Hypoxia + it’s different causes

Answer 4

oxygen deprivation
- hypoxaemic hypoxia - arterial content of oxygen is low
- anaemic - decreased ability of haemoglobin to carry oxygen
- ischaemic interruption to blood supply
- histiotoxic inability to utilise oxygen due to disabled oxidative phosphorylation enzymes (much rarer)

different tissues are affected in different ways by hypoxia ie neurones are affected very quickly, leading to cardiac arrest, however skeletal muscle can tolerate up to a few hours.
☞ cause needs to be determined in order to treat effectively

Question 5

Causes of cell injury: Examples of some toxins

Answer 5

• Poisions
• Pollutants
• Insecticides
• Herbicides
• Asbestos
• Alcohol
• Drugs

Question 6

Causes of cell injury: immune mediated

Answer 6

Two types of mechanism
hypersensitivity
- Excessive immune response to a non-self antigen
- Eg anaphylaxis

autoimmune
- Immune system over reacts to a self antigen
- Eg Grave’s disease

Question 7

Causes of cell injury: physical agents

Answer 7

• Trauma
• Extreme temperatures eg burns + frostbites
• Electric currents
• Radiotherapy
  also, infections: viral, fungal, bacterial, parasitic

Question 8

Causes of cell injury: nutritional

Answer 8

• Obesity
• Anorexia
• Any dietary deficiencies or excess eg B12, folate, vit D, salt, fat etc

Question 9

Causes of cell injury: genetic + ageing

Answer 9

• Inborn errors of metabolism
• Enzyme deficiencies
• Dysfunctional proteins

Question 10

What are the main different mechanisms of cell injury

Answer 10

lots of different types, but most result in a lack of ATP
- Depletion of ATP
- Direct mitochondrial damage
- Direct membrane damage
- Disruption to calcium homeostatis
- Oxidative stress (ie free radicals)
- Direct damage to DNA and proteins

Question 11

Mechanisms of cell injury: cellular reduction in ATP

Answer 11

cells deprived of oxygen → reduction in oxidative phosphorylation → mitochondrial ATP production stops
Cellular reduction in ATP has multiple effects:
- anaerobic glycolysis: intracellular glycogen stores depleted → inc lactic acid + phosphates → decreased pH in cell → denaturation → activity of enzymes effected
- Na/K pump: sodium + water enter cell → swelling of cell/organelle → potassium leaves cell → ER + cell swelling, loss of microvilli + blebbing → calcium also enters cell
- ribosomes detach from ER: reduced protein synthesis → altered metabolism → intracellular accumulations eg lipid deposition + denatured proteins

Question 12

How does calcium influx cause irreversible cell damage

Answer 12

Excess calcium can activate the following enzymes
- ATPases: reduces ATP in the cell further
- Phospholipases: break down cell and organelle membranes (and lysosome enzymes, so cell digests itself)
- Proteases: breaks down proteins, leading to dysfunctional proteins
- Endonucleases: breaks down DNA in cell

Question 13

Mechanisms of cell injury: free radicals

Answer 13

• aka oxidative stress
• free radical is atom with unpaired electron, highly reactive + chemically unstable
• formation can be pathological or physiological

Question 14

some common free radicals (aka reactive oxygen species, ROS

Answer 14

hydroxyl OH*
superoxide O2-
hydrogen peroxide H2O2

Question 15

Some examples of how free radicals are generated (no detail)

Answer 15

• chemical/radiation injury
• ischaemia-reperfusion injury
• cellular aging
• anti-microbial killing by phagocytosis

Question 16

How do free radicals damage lipids, proteins + DNA

Answer 16

lipid damage
- Free radicals target unsaturated fatty acids
- Causes cell membrane + DNA damage
- Results in calcium influx + damage to Na/K pump etc

protein damage
- Promotes protein-protein cross links (ie disulphide bonds)
- Promotes oxidation of proteins
- Causes protein fragmentation and therefore cell damage

DNA damage
- Free radicals target nuclear and mitochondrial DNA
- Cause single + double strand breaks in DNA
- This can cause cell aging and malignant transformation of cells

Question 17

Body control of free radicals (ie how do we get rid of them)

Answer 17

free radicals are so unstable that they commonly decay spontaneously in the presence of water or via
- Anti-oxidants: eg lipid soluble vitamins, ascorbic acid, glutathione
- Transport proteins: iron binds to transferrin, copper binds to ceruloplasmin (metals can cause free radical formation, but this is prevented by them binding to transport proteins)
- Enzymes: superoxide dismutases (SODs) and glutathione peroxidase
- Heat shock proteins eg ubiquitin: they help repair + refold damaged proteins, or label them for degradation

Question 18

What transport protein binds to iron and copper

Answer 18

• Iron binds to transferrin
• Copper binds to ceruloplasmin

Question 19

What are some reversible and irreversible damage to cells (and what are they due to, broadly speaking)

Answer 19

reversible
- Swelling (due to Na/K+ pump failure, so water into cell)
- Clumped chromatin (due to reduced pH)
- Ribosome dispersion (lack of ATP to hold them together)
- Cytoplasmic blebs (symptomatic of cell swelling)
☞ cell membrane is intact

irreversible
- Nuclear changes
- Lysosome rupture (reflects membrane damage)
- Membrane defects
- Lysis of endoplasmic reticulum (due to membrane defects)

Question 20

What is the difference between apoptosis and necrosis

Answer 20

apoptosis
- Cell suicide
- Individual programmed cell death
- Pathological or physiological
- Cells shrink, no inflammation
- Cell membrane preserved

necrosis
- Cell murder
- Cells swell
- Pathological
- Inflammation due to release of cell contents

Question 21

Physiological vs pathological apoptosis

Answer 21

physiological
- Embryogenesis
- Involution of hormone dependent tissue
pathological
- Cell death in viral infection
- Cells with damaged DNA

Question 22

Intrinsic vs extrinsic apoptosis

Answer 22

intrinsic (mitochondrial)
Mitochondria release cytochrome C → which activate caspases (enzymes) → induce apoptosis

extrinsic (death receptors) death receptors are released from T-killer cells → recognise damaged cells → attach to cell membrane → activate caspases → lead to cell death

Question 23

What is necrosis

Answer 23

in a living organism, the morphological changes that occur after a cell has been dead some time
- Seen after 12-24 hours
- See both macroscopically + microscopically
- Cells swell
- Causes lots of inflammation due to emptying of cell contents

Question 24

Different subtypes of necrosis

Answer 24

• coagulative occurs in solid organs, retains ghost outline of cells + tissue architecture. Protein denaturation prominent in the cell injury/death.
• liquefactive damage of ‘loose’ tissue, complete loss of architecture, release of enzymes that break down tissue.
• caseous seen in the lung (and sometimes lymph nodes) infected with TB. Cheese like.
• fat necrosis direct trauma to fatty areas. Acute pancreatitis.
• fibrinoid necrosis death of cells in small blood vessels

Question 25

What are some of the characteristic nuclear changes in necrosis

Answer 25

• pyknosis = shrinking of nucleus
• karyorrhexis = fragmentation of nucleus
• karyolysis = dissolution of nucleus (nucleus no longer seen in stained samples)

Question 26

What are the main molecules released by injured cells that can be tested for in the blood.

Answer 26

• potassium released by all dead cells that undergo necrosis. Cardio-toxic: too much will stop the heart. Also get high levels released in burns, major trauma and heart attacks.
• enzymes specific cells release specific enzymes – eg liver, pancreas + heart. Eg troponin released by heart, amylase released by pancreas in pancreatitis.
• myoglobin released by muscles. Eg in elderly patient who has fallen (lay on muscles, reduced blood flow to the muscles, muscles become hypoxic, muscles start to die), and also seen in athletes. Myoglobin is toxic to the kidneys → rhabomyolosis (tea coloured urine)

Question 27

Molecules retained by injured cells

Answer 27

cell injury causes deranged metabolism → intra-cellular accumulations
These accumulations can be:
- normal cell components eg water (leading to cerebral oedema)
- abnormal components eg fatty liver disease (fat accumulation within hepatocytes)
- pigment eg tattoo pigment into skin → pigment phagocytosed by macrophages → pigment remains in macrophages in dermis

Question 28

Cerebral oedema mechanism

Answer 28

• Swollen brain
• Eg cardiac arrest → not enough oxygen delivered to brain
• Hypoxic injury to neurones in brain → reduced ATP
• Na/K pump not working → water enters cells
• Water causes brain to swell
  ☞ in swollen brain, can’t see folds in brain
  ☞ compression against skull, causing less blood flow (ischaemic hypoxia)
  ☞ eventually causes necrosis of the brain, irreversible

Question 29

gangrene

Answer 29

☞ a necrosis visible to the human eye
- dry is a necrotic area exposed to air. Typically coagulative necrosis.
- wet is necrotic tissue that then becomes infected. Typically liquetive necrosis.
- gas is an infected area, tissue dies and then becomes infected by anaerobic bacteria. Usually seen in road traffic accidents and the skin becomes puffy (gas underneath)

Question 30

infarction

Answer 30

☞ necrosis caused by reduction in the arterial blood flow (ie ischaemia)
☞ infarction can result in gangrene
☞ ischaemic necrosis

sometimes, in some places of organs have additional blood supply, and therefore infarction won’t be apparent so quickly

Question 31

white vs red infarct

Answer 31

macroscopic description

white
- No associated haemorrhage
- Occurs in solid organs (eg spleen, heart, kidney)
- Occlusion of an end artery (ie an artery supplying a specific area of tissue, which then dies)
- Often wedge shaped

red
- Haemorrhage into dead tissue
- Organs with dual blood supply eg lungs and intestines
- Previous vascular congestion

Question 32

Definition: ischaemia

Answer 32

inadequate blood supply to tissue
Can result in infarction

Question 33

Pathological calcification

Answer 33

abnormal deposition of calcium within tissues
localised in dying tissues
- Aka dystrophic calcification
- Quite common
- Nothing to do with calcium metabolism

generalised
- Aka metastatic
- Deposition in otherwise normal tissues
- Could be due to metabolic error causing high levels of circulating calcium
- Can be fatal