Lecture 7: Irreversible effects

Question 1

2 Categories of cell death

Answer 1

Accidental and programmed (necrotic and apoptosis)

Question 2

Apoptosis

Answer 2

• Part of normal physiological maintenance of organs.
• Non-inflammatory
• Requires ATP and has cascade of steps
• Single cell death

Visible by:
- cell rounding, shrinkage, fragmentation into apoptotic bodies (immune cells eat them up), DNA/chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis), membranes and organelles left intact.

Question 3

Pyknosis

Answer 3

Chromatin/DNA condensation

(during apoptosis)

Question 4

Karyorrhexis

Answer 4

Nuclear fragmentation

(during apoptosis)

Question 5

What is apoptosis triggered by?

Answer 5

• Extracellular signal/ligand (FasL) binding to Fas (Death) receptors on cell membrane
• Loss of growth factors
• Detachment from ECM (anoikis), loss of function and structure - cell wonders around body - cancer.
• Oxidative stress (ROS) or ER stress
• Microtubule (important for cell division) or DNA damage

Question 6

Anoikis

Answer 6

Detachment from ECM - loss of function and structure

Question 7

How is apoptosis carried out

Answer 7

Smac and Cytochrome C (pro-apoptotic molecules) are released from stress induced mitochondria.

They activate APAF1 proteins to form the apoptosome complex, activating further downstream proteins - initiator caspase by oligomerisation.

Smac inhibits IAP (an anti-apoptotic caspase inhibitor). Activation of initiator and then effector caspases.

Effector caspase casues proteolytic protein cleavage, leads to apoptotic body formation. Apoptotic bodies are coated in Phosphotidyl Serine (PS), ‘eat me’ signal for phagocytes.

Once eaten, macrophages decrease TNF (pro-inflammatory), and increase TGFb (anti-inflammatory).

Question 8

Tumour Necrosis Factor (TNF)

Answer 8

Inflammatory signal, death inducing cell signal (necrosis).

Question 9

Transforming growth factor beta (TGFb)

Answer 9

Anti-inflammatory signal

Question 10

Inadequate apoptosis

Answer 10

Leads to autoimmune diseases (self-reactive immune cells are not eliminated) and cancers (cell accumulation)

Question 11

Excessive apoptosis

Answer 11

Acute ischemic injury to heart (myocardial infraction) and brain (stroke).

Chronic heart failure (cardiomyocytes) and neurodegeneration (alzheimer’s and parkinson’s).

Question 12

Necrotic cell death types:

Answer 12

Necroptosis, Pyroptosis, Ferroptosis

Question 13

Necrotic cell death:

Answer 13

Structural change that follows large scale cell death.

Inflammatory, emergency death caused by stressful environment. Many forms are also regulated.

ATP independent, membrane permeabilisation, and cell lysis. Sometimes visible cell swelling (oncosis), leakage of intracellular components. Repair of damaged tissue by scarring.

Question 14

Oncosis

Answer 14

Cell Swelling

Question 15

Necroptosis

Answer 15

‘Necro’ - death inducing protein ligands (i.e. TNF and FasL).

Receptor interacting protein kinases (RIPK) form necrosome complex, which induces oligomerisation of a protein that causes pores in the cell membrane. Resulting in leaky cell membrane.

Question 16

Necrostatins

Answer 16

RIPK1 inhibitors that suppress cell death (preventing leaky membrane). Suppresses inflammation and loss of function.

Question 17

Pyroptosis

Answer 17

‘pyro’ - fire. Triggered by fever or intracellular bacterial infection. Damage signals trigger inflammasomes.

Inflammasomes and caspases cleave:

Pro-IL-1b –> IL-1b –> PRO-inflammatory cytokine.
Gasdermin proteins to form pores in membranes.

Purpose: cell lysis prevents replication of intracellular bacteria and pro-inflammatory signals alert immune cells of the presence of pathogens.

Question 18

Ferroptosis

Answer 18

‘ferro’ - triggered by ROS and iron.

Process regulated by GPX4 which uses gutathione (GSH) as a reducing agent.

p53 can induce ferroptosis by suppressing GSH synthesis.

Question 19

Autophagy

Answer 19

Intracellular proess used to degrade intracellular pathogens, aggregated proteins, or damaged organelles.

Membrane bound vacuoles form and enclose the content, fuse with lysosomes (containing hydrolases). Vacuoles are degraded when cell is starved from nutrients to generate energy.

Phagophore (half forming vacuole) –> autophagosome (formed + lysosome –> autolysosome –> degradation.

Question 20

Causes of necrosis

Answer 20

Ischemia, Infection, Fat necrosis.

Question 21

Coagulative necrosis

Answer 21

• Due to ischemia
• lack of blood flow and oxygen to tissue.
• dead tissue retains its architecture becayse lysosomes don’t release their proteolytic enzymes immediately.
• necrotic tissue removed by inflammatory reaction and replaced by scar.
• could occur in heart - myocardial infarction.

Question 22

Colliquative (liquefactive) - Ischemia

Answer 22

Cellular lysosomes are damaged and release their hydralases which digest a tissue. Tissue turns into a soft, sircumscribed (wrapped in cyst wall) lesion. Leads to a blood filled space in the damaged tissue.

i.e. cerebral artery collusion (Stroke) leading to brain ischemia.

Question 23

Gas gangrene (rotting) - ischemia

Answer 23

Caused by deep injury trauma, damaging blood supply, leading to infection with anaerobic bacteria which can survive (doesnt need O2). Tissues feel crackly cus of CO2 produced by bacteria.

Black tissue - haemoglobin in blood is downgraded and iron sulphide is deposited. CO2 causes holes in tissue (cysts). Loss of nuclei and retention of protein, loss of architecture and function.

Question 24

Dry Gangrene (mummification) - ischemia

Answer 24

Occurs with slow ischemia (long term). Leads to necrosis, desiccation (drying up/mummification) and discolouration from breakdown of blood.

i.e. progressive narrowing of arteries by atherosclerosis (caused by diabetes and smoking).

Question 25

Suppurative (pus-forming) - infection

Answer 25

Infections lead to neutrophils releasing hydrolases that liquify tissue and form abscesses (boils) and cysts (sac filled with liquid).

i.e. aspergillus fungal infection of the lung - inhaled

Question 26

Caseous (cheese-like) infection

Answer 26

Formation of granulomas - consist of macrophages and neutrophils which surround bacteria. Leads to an area of central necrosis of lysed immune cells, tissue and bacteria. Caseous necrosis is amorphous (lacking clear shape), lipid and protein rich,

Question 27

Fat necrosis

Answer 27

Occurs which injury to adipose tissue and fat containing cells (with steatosis). Tissue injury leads to release of proteases and phospholipases that digest cell membranes and lipases that digest intracellular triglycerides. Fatty acids precipitate to form white opaque soaps.

Question 28

senescent cells

Answer 28

cells that stop dividing but don’t die