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1
Q

List the causes of cell injury

A
  • Hypoxia
  • Chemical agents and drugs
    • e.g. glucose or salt in hypertonic solutions, oxygen in high concentrations, poisons, insecticides, herbicides, asbestos, alcohol, illicit drugs, therapeutic drugs.
  • Infections
    • viruses, bacteria, fungi, other parasites.
  • Immunological agents
    • These cause injury principally by two mechanisms; hypersensitivity reactions where the host tissue is injured secondary to an overly vigorous immune reaction, e.g. urticaria (= hives) and autoimmune reactions where the immune system fails to distinguish self from non-self, e.g. Grave’s disease of the thyroid.
  • Dietary imbalance
  • Genetic abnormalities
    • inborn errors of metabolism
  • Physical agents
    • direct trauma, extremes of temperature (burns and severe cold), sudden changes in atmospheric pressure, electric currents, radiation.
2
Q

Describe Hypoxia

A
  • Oxygen deprivation results in decreased aerobic oxidative respiration which if persistent will cause cell adaptation (e.g. atrophy), cell injury or cell death.
  • The length of time a cell can tolerate hypoxia varies: neurones can only tolerate a few minutes while dermal fibroblasts can tolerate a number of hours.
3
Q

What are the causes of hypoxia?

A
  • Hypoaxaemic: arterial content of oxygen is low e.g. reduced inspired pO2 at altitude
  • Anaemic: decreased ability of haemoglobin to carry oxygen e.g. anaemia, carbon monoxide poisoning
  • Ischaemic: interruption to blood supply e.g. blockage of a vessel, heart failure
  • Histiocytic: inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzyme (cyanide poisoning)
4
Q

What is Ischaemia?

A
  • Loss of blood supply due to reduced arterial supply eg. obstruction of an artery, hypotension, OR reduced venous drainage
  • This causes a reduced supply of oxygen and metabolic substrates e.g. glucose for glycolysis and the resultant injury, therefore, occurs more rapidly and is more severe than that seen with hypoxia.
5
Q

Difference between reversible and irreversible cell injury

A
6
Q

What the four essential cell component that are the principal targets of cell injury?

A
  1. The plasma membrane, effectively the skin of the cell, which plays an essential role in homeostasis and the organellar membranes which compartmentalise organelles such as lysosomes (particularly important as they contain potent enzymes that can themselves cause cell damage).
  2. The Nucleus which contains the genetic material of the cell.
  3. The structural proteins forming the cytoskeleton and enzymes involved in the metabolic processes of the cell.
  4. Mitochondria where oxidative phosphorylation and production of ATP occurs
7
Q

Reversible vs irreversible injury (diagram)

A
8
Q

Describe Reversible Hypoxic Injury

A
  • Oxygen deprivation leads to decreased production of ATP in mitochondria. When the levels of ATP drop to less than 5-10% of normal concentrations, vital cellular functions become compromised.
  • Loss of activity of the Sodium Pump (ATP-dependent). As the intracellular concentrations of Na+ rises, water enters the cell and the cell and its organelles swell up. Ca2+ also enters causing damage to cell components.
  • The cell switches to the glycolytic pathway of ATP production leading to accumulation of lactic acid, lowering the pH inside the cell. Low pH affects the activity of many enzymes within the cell. Chromatin clumping occurs.
  • Ribosomes detach from the ER and protein synthesis is disrupted. This can result in intracellular accumulations of substances such as fat and denatured proteins.
9
Q

What does Irreversible Hypoxic Injury mean and when does it occur?

A
  • Not well understood but at some point, injury becomes irreversible and cell eventually dies
  • Usually appears as necrosis
  • Development of profound disturbances in membrane integrity and the associated massive cytosolic accumulation of Ca2+ is a key event
10
Q

What happens when Ca2+ enters the cell across the damaged plasma membrane and is released from intracellular stores in severely damaged cells?

A

Activate an array of potent enzymes:

ATPases (decrease [ATP} even further)

Phospholipases (causes further embrane damage)

Proteases (break down membranes and cytoskeletal proteins)

Endonucleases (damage DNA)

When lysosomal membranes are damaged their enzymes leak into the cytoplasm further damaging the cell

When Ca2+ enters cells whose membranes are irreversibly damaged, intracellular substances leak into the circulation. These can be detected in blood samples and particular substances can be indicative of the location of cellular damage e.g if liver cells are injured, transaminases will be detected in the blood.

11
Q

summary of hypoxic cell

A
  1. Cell is deprived of oxygen.
  2. Mitochondrial ATP production stops.
  3. The ATP-driven membrane ionic pumps run down.
  4. Sodium and water seep into the cell.
  5. The cell swells, and the plasma membrane is stretched.
  6. Glycolysis enables the cell to limp on for a while.
  7. The cell initiates a heat-shock (stress) response (see below), which will probably not be able to cope if the hypoxia persists.
  8. The pH drops as cells produce energy by glycolysis and lactic acid accumulates.
  9. Calcium enters the cell.
  10. Calcium activates:
  • phospholipases, causing cell membranes to lose phospholipid, proteases, damaging cytoskeletal structures and attacking membrane proteins,
  • ATPase, causing more loss of ATP,
  • endonucleases, causing the nuclear chromatin to clump.
  1. The ER and other organelles swell.
  2. Enzymes leak out of lysosomes and these enzymes attack cytoplasmic components.
  3. All cell membranes are damaged and start to show blebbing.
  4. At some point the cell dies, possibly killed by the burst of a bleb.
12
Q

What is Ischaemia-Reperfusion Injury?

A

If blood flow is returned to a tissue which has been subject to ischaemia but isn’t yet necrotic, sometimes the tissue injury that is then sustained is worse than if blood flow was not restored. This is called ischaemia-reperfusion injury.

It may be due to:

  • Increased production of oxygen free radicals (see below) with reoxygenation.
  • Increased number of neutrophils following reinstatement of blood supply resulting in more inflammation and increased tissue injury.
  • Delivery of complement proteins and activation of the complement pathway.
13
Q

What are free radicals?

A
  • Free radicals are reactive oxygen species.
  • They have a single unpaired electron in an outer orbit.
  • This is an unstable configuration and because of this free radicals react with other molecules, often producing further free radicals.
  • Free radicals are particularly produced in chemical and radiation injury, ischaemia-reperfusion injury, cellular ageing, and at high oxygen concentrations.
14
Q

3 free radicals of significance

A

Three free radicals are of particular biological significance in cells:

  • OH (hydroxyl, the most dangerous),
  • 02- (superoxide) and
  • H2O2 (hydrogen peroxide).
15
Q

What is the importance of free radicals?

A
  • Present in low concentration in normal state. Required for killing bacteria and also in cell signalling
16
Q

How does the body deal with free radicals?

A
  • Enzymes: Superoxide dismutase (SOD) catalyses the reaction O2- → H202. H2O2 is significantly less toxic to cells. Catalases and peroxidases complete the process of free radical removal: H202 → 02 + H20
  • Free radical scavengers that neutralise free radicals. Vitamins A, C and E and glutathione are free radical scavengers.
  • Storage proteins that sequester transition metals in the extracellular matrix. Transferrin and ceruloplasmin sequester iron and copper, which catalyse the formation of free radicals.
17
Q

What are Heat Shock proteins

A
  • When the folding step in protein synthesis goes astray or when proteins become denatured during cell injury, heat shock proteins ensure proteins are re-folded correctly.
  • If this isn’t possible, then the misfolded protein is destroyed.
  • Important in cell injury as heat shock response plays a key role in maintaining protein viability and thus maximising cell survival.

example is e.g ubiquitin

  • All cells (so far tested) from any organism (animals or plants) when submitted to stress turn down their usual protein synthesis and turn up the synthesis of HSPs.
18
Q

Morphology of cell injury: light microscope vs electron microscope

A
19
Q

Describe the Reversible Morphological Changes Under Light Microscopy

A
  • Reduced pink staining of the cytoplasm due to accumulation of water
  • Chromatin is subtly clumped
  • Abnormal intracellular accumulations
20
Q

Describe the Irreversible Morphological Changes Under Light Micrsoscopy

A
  • Increased pink staining due to detachment and loss of ribosomes from the ER and accumulation of denatured proteins.
  • After chromatin clumping, various combinations of pyknosis, karyorrhexis and karyolysis follow
    • Pyknosis: shrinkage due to condensation of chromatin
    • Karyorrhexis: fragmentation
    • Karyolysis: the dissolution of the nucleus
21
Q

Define Oncosis

A

The spectrum of changes that occur in injured cells prior to death - cell death with swelling

22
Q

Define Apoptosis

A

Cell death induced by a regulated intracellular program where cell activates enzymes that degrade it’s own nuclear DNA and proteins. Cell death with shrinkage; cell induced suicide

23
Q

Define Necrosis

A

The Morphological changes that follow cell death in living tissue, largely due to the progressive degradative action of enzymes on a lethally injured cell. ‘What the tissue looks like’

24
Q

When is necrosis seen?

A
  • When there is damage to cell membranes (plasma and organelle) and lysosomal enzymes are released into the cytoplasm and digest the cell. As a result cell contents leak out of the cell and inflammation is often seen.
  • Changes develop over a number of hours.
  • Eventually, necrotic tissue is removed by enzymatic degradation and phagocytosis by white cells.
  • If some necrotic remains, it may calcify - the process is called DYSTROPHIC CALCIFICATION
25
Q

What is Coagulative necrosis?

A
  • Commonest form
  • Occurs in most organs •
  • A result of protein denaturation
  • Gross: texture firm initially, can be soft later on
  • White in appearance
  • Microscopy-outline of cells preserved as surrounding stroma is more resistant to dissolution
  • Nuclear details and cytoplasmic details lost.
  • Neutrophils can infiltrate
  • commonest cause: ischaemia

When protein denaturation is dominant over the release of active proteases, the proteins tend to clump together leading to the solidity of dead cell and consequently of the dead tissue

26
Q

What is Liquefactive Necrosis?

A
  • Usually seen in brain
  • Seen in infections resulting in abscess formation
  • Degradation of tissue by enzymes.
  • The necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus

When the release of active enzymes, especially proteases is dominant over protein denaturation, the dead cells and consequently the dead tissue tends to liquefy.

27
Q

What is caseous necrosis?

A
  • “Cheese like” gross appearance
  • Amorphous debris surrounded by histiocytes resulting in a granulomatous inflammation
  • no outline as seen in coagulative necrosis

Associated with infections eg TB

It is also associated with a specific inflammation known as granulomatous

28
Q

What is fat necrosis?

A
  • Destruction to adipocytes as a consequence of trauma or secondary to release of lipases from damaged pancreatic tissue.
  • Fat necrosis causes fatty acids which react with calcium to form white deposits in fatty tissue.
  • Seen in breast tissue and can mimic breast tumour on radiology and is biopsied to exclude cancer.
29
Q

What i fibrinoid necrosis?

A
  • Usually seen in immune reactions involving blood vessels.
  • Deposits of “immune complexes,” together with fibrin that has leaked out of vessels.
  • Bright pink and amorphous appearance in H&E stains, called“fibrinoid” (fibrin-like) by pathologists
30
Q

Define Gangrene

A
  • Clinical term to describe necrosis visible to the naked eye (macroscopic)
  • Dry, Wet, Gas
  • Gangrene is mot commonly seen in ischemic limbs
  • A gangrenous tissue is dead and therefore cannot be salvaged.
31
Q

Describe Dry, Wet and Gas Gangrene

A
  • Dry gangrene in which the underlying proess is coagulative ncrosis
  • Wet gangrene is see with liquefactive necrosis. Typically due to infection and is very serious as it can result in septicaemia
  • Gas is a particular type of wet gangrene; tissue has become infected with anaeobic bacteria which produces bubbles of gas.
32
Q

What does Infarction mean?

A
  • Refer to a cause of necrosis, namely Ischaemia
  • An area of tissue death caused by an obstruction of a tissue’s blood supply is an infarct.
  • Infarction can result in gangrene.
  • Most infarctions are due to thrombosis or embolism. Can occasionally be due to external compression of a vessel e.g. by a tumour or within a hernia
  • Can be coagulative or liquefactive
    • ischaemic necrosis in the heart (MI) shows coagulative necrosis
    • ischaemic necrosis in the brain shows liquefactive necrosis
  • Can be described as White or Red
33
Q

What is a White Infarct and where can it occur?

A
  • Anaemic (white) infarct occurs in solid organs with good stromal support after occlusion of an end artery (sole source of arterial blood).
  • The solid nature limits the amount of haemorrhage that can occur into the infarct from adjacent capillaries.
  • The tissue supplied by the end artery dies and appears pale/white due to lack of blood in the tissue
  • Can occur in heart, spleen and kidneys
  • Most are wedge-shaped with the occluded artery at the apex of the wedge
  • Histologically, white infarcts appear as coagulative necrosis
34
Q

What is Red Infarct and where does it occur?

A
  • Haemorrhagic infarct occurs when there is extensive haemorrhage into dead tissue:
  • In organs with a dual blood supply e.g. lung. Occlusion of the main arterial supply causes an infarct. The second arterial supply is insufficient to rescue the tissue but does allow blood to enter the dead tissue.
  • If numerous anastomoses (where the capillary beds of two separate arterial supplies merge) are present within the tissues e.g. intestines
  • In loose tissue e.g. lung where there is poor stromal support for capillaries and therefore there is more than usual haemorrhage into the dead tissue
  • When there has been previous congestion e.g. in congestive cardiac failure, tissues can be congested and there is more than the usual amount of blood in the necrotic tissue
  • Where there is raised venous pressure
35
Q

How can raised venous pressure cause a red infarct?

A

Increased pressure is transmitted to the capillary bed. As the tissue pressure increases, eventually, there is reduced arterial filling pressure in the tissue which causes ischaemia and subsequent necrosis. Because the tissue was engorged with blood, the resulting infarct is red.

36
Q

What are the molecules released by Injured and Dying Cells?

A

Calcium

Potassium

Enzymes

Myoglobin

37
Q

Why is measuring enzymes useful?

A

Can help with the timing and evolution of tissue damage

Enzymes with the lowest molecular weight are released first

Particularly applies to heart and liver; measurement of enzymes can be used to follow progress and find location (on organ) of damage

38
Q

What is apoptosis?

A
  • Programmed cell death
  • Characteristic non random internucleosomal clevage of DNA
  • Distinct morphological features
39
Q

Describe the Initiation and Execution Phases of Apoptosis

A

Triggered by two key mechanisms intrinsic and extrinsic which both culminate in the activation of caspases.

40
Q

What is the intrinsic mechanism?

A
  • mitochondrial
  • All the apoptotic machinery is within the cell and the mitochondrion is a key player.
  • There are various triggers for intrinsic apoptosis (e.g. DNA damage or the withdrawal of growth factors or hormones)
  • p53 is important
  • The triggers lead to increased mitochondrial permeability resulting in the release of Cytochrome C from mitochondria. This interacts with APAF1 and caspase 9 to form an apoptosome that activates various downstream caspases
41
Q

What is the extrinsic mechanism?

A
  • Aka receptor-mediated apoptosis
  • Caused by external ligands such as TRAIL or Fas which bind to death receptors.
  • This leads to caspase activation independently of mitochondria
42
Q

What are Caspases?

A
  • Proteases that mediate the cellular effects of apoptosis.
  • They act by cleaving proteins, breaking up the cytoskeleton and initiating the degradation of DNA.
43
Q

Describe the Degradation/Phagocytosis Phase of Apoptosis

A

Cell breaks into membrane-bound fragments called apoptotic bodies.

They express molecules on their surfaces that induce the phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes.

44
Q

What are some important apoptotic molecules?

A
  • p54: mediates apoptosis in response to DNA damage
  • Cytochrome C, APAF1 and Caspase 9 together are apoptosomes
  • Bcl-2 prevents cytochrome C release from mitochondria therefore INHIBITING apoptosis
  • Death ligands e.g. TRAIL
  • Death receptors e.g. TRAIL-R
  • Caspases: effector molecules of apoptosis e.g. Caspase 3
45
Q
A
46
Q

Necrosis Vs Apoptosis

A
47
Q

five main groups of intracellular accumulation

A
  • water and electrolytes
  • lipids
  • proteins
  • pigments
  • carbohydrates