Cell Injury Flashcards
What is pathology?
The study of suffering
What does pathology investigate?
The structural and functional changes in cells, tissues, and organs that are seen in disease.
It is the study of disease and cellular malfunction
What are diseases the result of?
Intrinsic abnormalities or external factors, or both
What is an intrinsic abnormality?
Genetic
Give an example of an external factor?
Infections
What does diagnostic pathology involve?
Studying the structural and functional alterations in cells and tissues in order to arrive at a diagnosis
What results in the symptoms and signs of a disease?
The morphological changes in cells and tissues and their distribution within an organ
What does all disease start with?
Molecular or structural alterations in cells
When are cells able to maintain homeostasis?
When subjected to mild changes in environmental conditions
What happens when environmental changes are more severe?
Cells undergo physiological and morphological adaptations in an attempt to remain viable
How may cells react to injury?
They may increase or decrease their level of activity
What does wether cells increase or decrease their activity with injury depend on?
The nature and intensity of the injury
How may a cell increase its level of injury?
Hyperplasia
How may a cell decrease its level of activity?
Atrophy
What happens when cells reach their limits of adapative response?
They may show evidence of reversible injury, or become irreversibly injured and due
What does the degree of cell damage depend on?
Type, duration and severity of an injury, and the type of tissue thats involved
How was it discovered that cells are the basic unit of the body?
Through the microscope
Where does the ultimate abnormality lie in disease?
The cell
What can damage cells?
Hypoxia Physical agents Chemical agents and drugs Micro-organisms Immune mechanisms Dietary insufficiency and deficiencies, and dietary excess Genetic abnormalities
What is hypoxia?
Oxygen deprivation
What does hypoxia result in?
Decreased aerobic oxidative respiration
How can energy production continue in hypoxia?
Through glycolytic energy production
What happens if hypoxia is persistent?
Cell adaptation, cell injury and cell death
What cell adaptation may be used in hypoxia?
Atrophy
How long can a cell tolerate hypoxia?
It varies
Some neurones can only tolerate a few minutes
Dermal fibroblasts can tolerate a number of hours
What is ischaemia?
A loss of blood supply due to reduced arterial supply or reduced venous drainage
What can cause a reduced arterial supply of blood?
Obstruction of an artery
Hypotension
What does ischaemia cause?
A reduced supply of oxygen and metabolic structure
What is the result of ischaemia also causing a decreased supply of metabolic substrates?
It occurs more rapidly and is more severe than seen with hypoxia
What can the causes of hypoxia be classified as?
Hypoxaemic
Anaemic
Histiocytic
Ischaemic
What is meant by hypoxaemic?
The arterial content of oxygen is low
Why may hypoxamia occur?
Reduced inspired pO2 at altitude
What happens in anaemic hypoxia?
There is a decreased ability of haemoglobin to carry oxygen
What can cause anaemic hypoxia?
Anaemia
Carbon monoxide poisioning
What causes ischaemic hypoxia?
Interruption to blood supply
What causes histiocytic hypoxia?
Inability to utilise oxygen in cells due to disable oxidative phosphorylation enzymes
What can cause histiocytic hypoxia?
Cyanide poisioning
What physical agents could cause cell injury?
Direct trauma Extremes of temperature (burns and severe cold) Sudden changes in atmospheric pressure Electric currents Radiation
What chemical agents and drugs can cause hypoxia?
Glucose and salt in hypertonic solutions Oxygen in high concentrations Poisons Insecticides Herbicides Asbestos Alcohol Illicit drugs Therapeutic drugs
What microorganisms can cause hypoxia?
Viruses
Bacteria
Fungi
Other parasites
How do immune mechanisms cause cell injury?
Hypersensitivity reactions
Autoimmune reactions
What happens in hypersensitivity reactions?
The host tissue is injured secondary to an overly vigorous immune reaction
Give an example of a hypersensitivity reaction
Urticaria (hives)
What happens in autoimmune reactions?
The immune system fails to distinguish self from non-self
Give an example of an autoimmune reaction
Grave’s disease of the thyroid
Give an example of a genetic abnormality that can cause cell injury
Inborn errors of metabolism
What are the principal targets of cell injury?
Cell membranes
Nucleus
Proteins
Mitochondria
What is the cell membrane important for?
The plasma membrane plays an essential role in homeostasis
The organellar membrane compartmentalise organelles
Why is the compartmentalisation of organelles by membranes important?
Because they contain potent enzymes that can themselves cause damage
What does the nucleus contain?
The genetic material of the cell
Why are proteins important in the cell?
Structural proteins form the cytoskeleton
Enzymes involved in the metabolic processes of the cell
What happens in the mitochondria?
Oxidative phosphorylation and production of ATP
What is the most common cause of cell injury?
Hypoxia and ischaemia
How is hypoxia similar to other types of other cell injury?
Many of the changes seen in hypoxia also occur in other causes (although the sequence of events may be different)
What happens as the cell becomes deprived of oxygen?
There is decreased production of ATP by oxidative phosphorylation in the mitochondria, and so the levels of ATP in the cell
At what level of ATP depletion do vital cellular functions become compromised?
When levels drop to less than 5-10% of normal concentrations
Why does a drop in cellular ATP levels cause vital cellular functions to become compromised?
There is a loss of activity of the Na/K plasma membrane pump.
With the lack of oxygen, the cell switches to the glycolitic pathway of energy production
Ribosomes detach from the endoplasmic reticulum (as energy is required to keep them attached)
What is the result of the loss of activity of the Na/K plasma membrane pump?
Intracellular concentration of Na rises, and so water enters the cell. This means the cell and its organelles swell up.
Ca also enters the cell, and this results in damage to cell components
What is the process of cell swelling called?
Oncosis
What is the problem with the cell switching to the glycolytic pathway of ATP production?
It results in an accumulation of lactic acid, which reduces the pH of the cell
What does the lowering of pH in the cell result in?
Affects the activity of many enzymes within the cell
Chromatin clumping is seen
What happens when ribosomes detach form the endoplasmic reticulum?
Protein synthesis is disrupted
What is the result of the disruption of protein synthesis due to detachment of ribosomes?
Can be intracellular accumulations of substances such as fat and denatured proteins
What happens at some point when a cell is injured?
The injury becomes irreversible and the cell will eventually die
How do most cells die in hypoxia?
Oncosis
What will happen when a cell has been irreversibly injured?
The tissue will eventually appear necrotic
What actually kills the cell in hypoxia?
It is not clear exactly what kills the cell, but a key event is the development of profound disturbances in membranes integrity and therefore an increase in membrane permeability followed by a massive influx of Ca into the cytoplasm
What level is cytosolic free Ca usually?
Usually at a very low level, as its kept within mitochondria and the endoplasmic reticulum
What happens to Ca when cells are severely damaged?
It enters the cell from outside, across the damaged plasma membrane, and it released from stores in the endoplasmic reticulum and mitochondria
Why is the influx of cytosolic Ca damaging?
Because calcium ions are biologically very active and high concentrations within the cytoplasm results in the activation of an array of potent enzymes such as ATPases, phospholipases, proteases and endonucleases
What is the problem with increased action of ATPases?
Decreases the concentrations of ATP further
What is the problem with increased action of phospholipases?
Causes further membrane damage
What is the problem with increased action of proteases?
Breaks down membrane and cytoskeletal proteins
What is the problem with increased action of endonucleases?
Damages DNA, causing nuclear chromatin to clump
What happens when lysosomal membranes are damaged?
Their enzymes leak into the cytoplasm further damaging the cell
What happens whilst Ca enters cells whose membranes are irreversibly damaged?
Intracellular substances leak out into the circulation
How can intracellular substances that have leaked into the circulation be detected?
In blood samples
What does the type of substance detected in blood samples indicate?
Where the cellular damage is occurring
Give a summary of hypoxic cell injury
- Cell is deprived of oxygen
- Mitochondrial ATP production stops
- ATP-driven membrane ionic pump runs down
- Sodium and water seep into the cell
- The cell swells, and the plasma membrane is stretched
- Glycolysis enables the cell to limp on for a while
- The cell initiates a heat-shock (stress) response
- The pH drops as the cells produce energy by glycolysis and lactic acid accumulates
- Calcium enters the cell
- Calcium activates phosholipases, proteases, ATPase and endonucleases
- The ER and other organelles swell
- Enzymes leak out of lysosomes and these enzymes attack cytoplasmic components
- All cell membranes are damaged and start to show blebbing
- At some point the cell dies, possibly killed by the burst of a bleb
What happens if blood flow is returned to a tissue that has been subject to ischaemia, but isn’t yet necrotic?
Sometimes the tissue injury sustained is worse than if blood flow was not restored
What is it called when a cell is injured because blood flow is returned after ischaemia?
Ischaemia-reperfusion injury
What may ischaemia reperfusion injury be due to?
Increased production of oxygen free radicals 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
How do some chemicals act to injure the cell?
By combining with a cellular component
How does cyanide act?
It binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation
What are free radicals?
A reactive oxygen species
What do free radicals have?
A single unpaired electron in an outer orbit
What is the problem with free radicals having a single unpaired electron?
It is an unstable configuration, and because of this free radicals react with other molecules, often producing more free radicals
When are free radicals particularly produced?
In chemical and radiation injury, ischaemia-reperfusion injury, cellular ageing, and at high oxygen concentrations
What do free radicals do to cells?
They attach lipids in cell membranes and cause lipid peroxidation
They can damage proteins, carbohydrates, and nucleic acids.
How can free radicals damage proteins, carbohydrates and nucleic acids?
They can become bent out of shape, broken or cross linked
What are free radicals known to be?
Mutagenic
Are free radicals always pathological?
No- they are also involved in many physiological events
What produces free radicals for physiological purposes?
Leukocytes
What physiological events are free radicals involved in?
Killing bacteria
Cell signalling
Which free radicals are of particular biological importance in cells?
OHº (hydroxyl)
O 2 - (superoxide)
H 2 O 2 (hydrogen peroxide)
What is the most dangerous free radical?
Hydroxyl (OHº)
How can hydroxyl be formed?
Radiation can directly lyse water
The Fenton and Haber-Weiss reactions
What is the Fenton reaction?
Fe 2+ + H 2 O 2 → Fe 3+ + OH - + OHº
What is the Haber-Weiss reaction?
O 2 - + H + + H 2 O 2 → O 2 + H 2 O + OHº
What do the Haber-Weiss and Fenton reactions show to be important?
The removal of superoxide and hydrogen peroxide rapidly, so the more dangerous hydroxyl can’t be formed
Where is the Fenton reaction important?
In injury where bleeding occurs
Why is the Fenton reaction important in injury where injury occurs?
As when blood is around, iron is available for the production of free radicals
What does the body have to prevent injury caused by free radicals?
Defence systems
What is the bodys defence system against free radicals known as?
The anti-oxidant system
What happens if there is an imbalance between free radical production and free radical scavenging?
Free radicals build up and the cell or tissue is said to be in oxidative stress
What does oxidative stress cause?
Cell injury
What does the antioxidant system consist of?
Enzymes
Free radical scavengers
Storage proteins
What enzymes are involved in the antioxidant system?
Superoxide dismutase (SOD)
Catalases
Peroxidases
What does SOD do?
Catalyses the reaction O 2 - → H 2 O 2
What is the advantage of SOD?
H 2 O 2 is significantly less toxic to cells
What do catalases and peroxidases do?
Complete the process of free radical removal?
H 2 O 2 → O 2 + H 2 O
What do free radical scavengers do?
Neutralise free radicals
Give 4 examples of free radical scavengers
Vitamins A, C and E
Glutathione
What do storage proteins do?
Sequester transition metals in the extracellular matrix
Give two examples of storage proteins?
Transferrin and ceruloplasmin
What do transferrin and cerulopasmin do?
Sequester iron and copper (which catalyse the formation of free radicals)
What are heat shock proteins (HSPs)?
Stress proteins, unfoldases, chaperonins
What is the heat shock response triggered by?
Any form of injury (not justhead)
Are HSPs found in unstressed cells?
Yes, in lower concentrations
What cells show the heat shock response?
All cells from any organism, animal or plant
What do cells do when submitted to stress?
Turn down their usual protein synthesis and turn up the synthesis of HSPs
What is shown by all organisms using HSPs?
They must play a key role in survival
Are HSPs secreted?
No, they remain within the cell
What are HSPs concerted with?
Protein repair (analogous to DNA repair)
When are HSPs important?
When the folding step in protein synthesis does astray, or when proteins become denatured during cell injury
What do HSPs recognise?
Proteins that are incorrectly folded
How do HSPs repair proteins?
By ensuring that they are refolded correctly
What happens if refolding of a damaged protein is not possible?
It is destroyed
Why are HSPs important in cellular injury?
As the heat shock response plays a key role in maintaining protein viability and thus maximising cell survival
Give an example of a HSP
Ubiquitin
What is the problem with determining when a cell died?
It is hard to identify cells that died minutes ago to hours ago, and hard to distinguish reversible injury from cell death. Histologic sections do not give us the time of cell death, and there is also little to be seen by the naked eye around the time of cell death
How is the diagnosis of cell death probably best made?
On functional rather than morphological criteria, e.g. increased permeability of the cell membrane
How can permeability of the cell membrane be assessed?
By the dye exclusion technique, where dye is put into the cells’ medium
What do the results of the dye exclusion technique mean?
It the dye doesn’t enter the cell, it’s alive.
If the cell soaks it up, they are dead
What 3 main alternations can be seen in cell death with swelling?
Cytoplasmic changes
Nuclear changes
Abnormal intracellular accumulations
What cytoplasmic changes are seen in cell death with swelling?
There is reduced pink staining of the cytoplasm.
This may be followed by increased pink staining.
Why is there reduced pink staining in cell death?
Accumulation of water
Is reduced pink staining a reversible change?
Yes
Why may there be a progression to increased pink staining?
Due to detachment and loss of ribosomes from the ER, and accumulation of denatured proteins
Is increased pink staining a reversible change?
No
What nuclear changes can be seen in cell injury?
Chromatin is subtly clumped
May be follow be various combinations of pyknosis, karryohexis, and karryolysis of the nucleus
Is subtle clumping of chromatin reversible?
Yes
What is pyknosis?
Shrinkage
What is karryohexis?
Fragmentation
What is karryolysis?
Dissolution
What reversible changes have been detected in cellular injury by the electron microscope?
Swelling
Cytoplasmic blebs
Clumped chromatin
Ribosome separation from the ER
What swells in reversible cell injury?
Both the cells and the organelles
Why is there swelling in cell injury?
Due to the Na/K pump failure
What are cytoplasmic blebs symptomatic of?
Cell swelling
What causes clumped chromatin?
Reduced pH
Why is there ribosome separation from the ER?
Due to failure of energy-dependant process maintaining ribosomes in the correct location
What irreversible changes have been detected in cellular injury by the electron microscope?
Increased cell swelling
Nuclear changes- pyknosis, karyolysis, karyorrhexis
Swelling and rupture of lysosomes
Membrane defects
Appearance of myelin figures
Lysis of the endoplasmic reticulum
Amorphous densities in swollen mitochondria
What does the swelling and rupture of lysosomes reflect?
Membrane damage
What are myelin figures?
Damaged membranes
What is lysis of the endoplasmic reticulum due to?
Membrane defects
In summary, what is cell swelling due to?
The failure of ionic pumps in the cell membrane through lack of energy supply
What is implied by cell swelling being due to failure of ionic pumps?
As well as occurring with hypoxia, oncosis would also be expected to occur with poisons that interfere with a cell’s energy metabolism or the integrity of the cell membrane
What happens as cells undergo oncosis?
They (and the tissue as a whole) increases in weight
What is oncosis?
Cell death with swelling
The spectrum of changes that occur prior to death in cells injured by hypoxia and some other agents
What is apoptosis?
Cell death with shrinkage
What is apoptosis induced by?
A regulated intracellular program where the cell activates enzymes that degrade its own nuclear DNA and proteins
What is necrosis?
In a living organism, the morphological changes that occur after a cell has been dead for some time, e.g. 4-24 hours
What are the changes in appearance seen in necrosis due to?
Largely the progressive degradative action of enzymes on the lethally injured cell
What does necrosis describe?
Morphological changes, it is NOT a type of cell death
What happens to the nucleus in oncosis?
It fades away by karyolysis
What happens to the nucleus in apoptosis?
It becomes very dense and breaks up (karyorrhexis)
When is necrosis seen?
When there is damage to the cell membranes (plasma and organelle), and lysosomal enzymes are released into the cytoplasm and digest the cell.
What is the result of lysosomal enzymes digesting the cell?
Cell contents leaks out, and inflammation is often seen
How long do necrotic changes take to develop?
Happens over a number of hours, e.g. it takes 4-12 hours until microscopic changes are seen after a myocardial infarction
What eventually happens to necrotic tissue?
It is removed by enzymatic degradation and phagocytosis by white cells
What may happen if some necrotic tissue remains?
It may calcify
What is the calcification of necrotic tissue called?
Dystrophic calcification
What are the two main types of necrosis?
Coagulative and liquifactive
What is liquifactive necrosis also known as?
Colliquitive
What can happen to cells proteins as cells are dying?
They can either undergo denaturation or autolysis
What tends to happen to denatured proteins?
They coagulate
What happens when proteins undergo autolysis?
They undergo dissolution by the cells own enzymes
When do protein lysis and coagulation start to occur?
When the cell is still alive
What determines which of the two main patterns of necrosis are seen?
The balance between the two key processes- coagulation and autolysis
What happens when protein denaturation is the dominant feature?
The proteins tend to ‘clump’, leading to solidity of the dead cells and consequently of the dead tissue. The net result is coagulative necrosis
What happens when release of active enzymes, particularly proteases, is the dominant feature?
The dead cells and consequently the dead tissue tends to liquefy, leading to liquifactive necrosis
What is seen in most solid organs when the cause of death is ischaemia?
Coagulative necrosis
What happens when cell death is associated with large numbers of neutrophils?
Their released proteolytic enzymes lead to liquifactive necrosis
Give an example of when necrotic changes might be harder to classify?
The pancreas typically shows coagulative necrosis, but being rich in proteolytic enzymes such as trypsin, the changes are modified to a certain extend
What are the two other types of necrosis that only occur under a limited set of circumstances?
Caseous and fat necrosis
Are gangrene and infarcts types of necrosis?
No
What dominates in coagulative necrosis?
Denaturation of proteins over release of active proteases
What consistency is the dead tissue in coagulative necrosis?
Solid
How does coagulative necrotic tissue appear to the naked eye?
White
What happens to the cells proteins in coagulative necrosis?
They uncoil and become less soluble
What happens histologically in coagulative necrosis?
The cellular architecture is somewhat preserved, creating a ‘ghost outline’ of the cells
When will the typical changes of coagulative necrosis be seen?
In the first few days
What happens to the appearance of coagulative necrosis after the first few days?
The appearances are modified by the fact that the dead tissues incite an inflammatory reaction with consequent infiltration by phagocytes
What happens in liquifactive necrosis?
Active enzymatic degradation is substantially greater than denaturation, and this leads to enzymatic digestion (liquefaction) of tissues
When is liquifactive necrosis seen?
In massive neutrophil infiltration
Give an example of necrosis where there would be massive neutrophil infiltration?
In abscesses
Why is their liquifactive necrosis when there is massive neutrophil infiltration?
Because neutrophils release proteases
What kind of infections is liquifactive necrosis seen in?
Bacterial
What organ is liquifactive necrosis seen in?
Brain
Why is liquifactive necrosis seen in the brain?
Because this is a fragile tissue without support from a robust collagenous matrix
What happens to the tissue in liquifactive necrosis?
If becomes a viscous mass, and if there is acute inflammation, pus is present
What is caseous necrosis characterised by?
Its amorphous debris
What is caseous necrosis particularly associated with?
Infections, especially TB
Granulomatous inflammation
What is fat necrosis seen?
When there is destruction of adipose tissue
When is fat necrosis most typically seen?
As a consequence of acute pancreatitis
Why is fat necrosis seen in acute pancreatitis?
As during inflammation of the pancreas there is a release of lipases from the injured pancreatic acinar cells. These lipases act on fatty tissues of the pancreas and on fat elsewhere in the abdominal cavity, causing fat necrosis
What does fat necrosis cause?
Release of free fatty acids, which can react with calcium to form chalky deposits (calcium soaps) in fatty tissue
How can calcium soaps be detected?
They can be seen on x-rays and with the naked eye at surgery and autopsy
What can fat necrosis occur after?
Direct trauma to a fatty tissue, especially breast tissue
Why is fat necrosis in the breast significant?
After it heals it leave an irregular scar that can mimic a nodule of breast cancer
What is gangrene?
A clinical term used to describe necrosis that is visible to the naked eye
NOT a type of necrosis
How can gangrene be further classified?
Into dry and wet gangrene
What does classification of gangrene depend on?
Wether the necrosis is modified by exposure to air resulting in drying (dry gangrene), or by an infection with a mixed bacterial culture (wet gangrene)
Can bacteria grow in dry tissue?
No
What is dry gangrene responsible for?
The dry, crisp appearance of the gangrenous umbilical cord stump after birth and gangrenous toes
What is the underlying process in dry gangrene?
Coagulative necrosis
What is the underlying process in wet gangrene?
Liquifactive necrosis
Why is wet gangrene, or infected necrosis, very serious?
As bacteria can easily get into the blood stream and it can result in septicaemia
What is gas gangrene?
Wet gangrene where the tissue has become infected with anaerobic bacteria that produce visible and palpable bubbles of gas within tissues
What is a typical scenario for gas gangrene?
The crushing of a limb in a motorcycle accident
How does gas gangrene arise with the crushing of a limb in a motorcycle accident?
The injured tissue loses it blood supply and becomes necrotic resulting in the appearance of gangrene. The tissue is colonised by anaerobic bacteria picked up from the soil and gas gangrene develops.
Where is gangrene most commonly seen in clinical practice?
Ischaemic limbs
Can gangrenous tissue be salvaged?
No, it is dead
What does infarction refer to?
A cause of necrosis, namely ischaemia
What is an infarct?
An area of tissue death caused by obstruction of a tissues blood supply
What can infarction result in?
Gangrene
What are most infarctions due to?
Thrombosis or embolism
What can infarctions occasionally be due to?
External compression of a vessel or by twisting of vessels
What may externally compress a vessel?
A tumour, or within a hernia
Give two examples of where vessels may be twisted?
Testicular torsion
Volvulus of the bowel
What type of necrosis is found in infarcted tissue?
Can be either
How can infarcts be described?
By their colour- white or red
What does the colour of an infarct indicate?
How much haemorrhage there is into the infarct
Where does a white (anaemic) infarct occur?
In ‘solid’ organs- those with good stromal support- after occlusion of an ‘end’ artery
What is an end artery?
Any artery that is the sole source of arterial blood to a segment of an organ
What is the result of the solid nature of the tissue in a white infarct?
It limits the amount of haemorrhage that can occur ito the infarct from adjacent capillaries
What happens to the tissue supplied by the end artery in a white infarct?
It dies, and appears pale/white because of the lack of blood in the tissue
Where do white infarcts occur?
In the heart, spleen and kidneys
What shape are most white infarcts?
Wedge-shaped, with the occluded artery at the apex of the wedge
How do white infarcts appear histologically?
As coagulative necrosis
When does a red (heamorrhagic) infact occur?
When there is extensive haemorrhage into dead tissue
When may there be extensive haemorrhage into dead tissue?
In organs with a dual blood supply
If numerous anastomoses are present within a tissue
In loose tissue
Where there has been previous congestion
Where there is raised venous pressure
Give an example of an organ with dual blood supply?
The lung
What happens when there is an occlusion of an artery in an organ with a dual blood supply?
Occlusion of the main arterial supply causes an infarct. The secondary arterial supply is insufficient to rescue the tissue, but does allow blood to enter the tissue, causing a red infarct
Where will there be numerous anastomoses?
Where the capillary beds of two separate arterial supplies merge
Give an example of an organ that has numerous anastomoses?
Intestines
Why does a red infarct occur when there are numerous anastomoses?
For the same reason as in organs with a dual blood supply
Give an example of an organ with loose tissue
The lung
Why do red infarcts occur in loose tissue?
There is poor stromal support for capillaries, and therefore there is more than usualy haemorrhage into the dead tissue
Give an example of where there may have been previous congestion?
In congestive cardiac failure
Why do you get red infarcts where there has been previous congestion?
There is more than the usual amount of blood in the necrotic tissue
Why does raised venous pressure cause red infarcts?
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
What are the consequences of an infarct?
Varying, ranging from none to death
What do the consequences of infarcts depend on?
Wether the tissue affected has an alternative blood supply
How quickly the ischaemia occurred
How vulnerable a tissue is to hypoxia
The oxygen content of the blood
Give 2 examples of places with alternate blood supplies
Lung
Forearm
What may happen if the ischaemia occurred slowly?
There is more time for the development of additional perfusion pathways
What may happen if an infarct occurs in an anaemic patient?
It may have more serious consequences
What happens as membranes lose their integrity?
Many molecules leak out of the injured cells
What are the consequences of molecules leaking out of injured cells?
They can cause local irritation and local inflammation
They may have general toxic effects on the body
They may appear in high concentrations in the blood
Why is the appearance of molecules in high concentrations in the blood important?
Because they can be measured and thus aid in diagnosis
What are the principal molecules released from injured cells?
Potassium
Enzymes
Myoglobin
What concentrations is potassium normally found in?
High concentrations in cells compared to extracellular fluid
In terms of potassium, how can a dying cell be considered?
As a ‘potassium bomb’
What happens to the heart with high potassium concentrations?
It stops beating
How can high potassium concentrations reach the heart?
From a myocardial infarction, or massive necrosis elsewhere in the body, e.g. severe burns, tourniquet shock or tumour lysis syndrome
When does tourniquet shock occur?
After a tourniquet is removed having been in place for several hours
What is tumour lysis syndrome?
The paradoxical result of successful chemotherapy, when a large mass of tumour cells becomes acutely necrotic
What can enzymes indicate?
The organ involved, and the extent, timing and evolution of tissue damage
What enzymes are released from injured tissue first?
Those with the smallest molecular weight
What is myoglobin released from?
Dead myocardium and striated muscle
What happens if large amount of myoglobin are released by damaged striated muscle?
A condition called rhabdomyolosis occurs
When is rhabdomyolysis seen?
In severe burns or trauma, strenuous exercise, with potassium depletion and with alcohol and drug abuse
What can happen to myoglobin released from striated muscle?
It can plug the renal tubules, resulting in renal failure
What is apoptosis?
The death of a single cell (or small cluster of cells) due to activation of an internally controlled suicide program
What can apoptosis be regarded a?
An equal and opposite force to mitosis
What is apoptosis characterised by?
It’s morphology, and by the type of DNA breakdown that occurs
What type of DNA breakdown occurs with apoptosis?
Characteristic, non-random, internucelosomal cleavage of DNA
How does the DNA breakdown in apoptosis differ from that in oncosis?
In oncosis, DNA is chopped into pieces of random length
When can apoptosis be a normal physiological process?
When cells are no longer needed, to maintain a steady state, during hormone-controlled involution and cytotoxic T cell killing of virus infected or neoplastic cells.
It is also seem in embryogenesis
What can cell death by apoptosis impart?
Shape
What particular type of cell damage would result in apoptosis?
When damage affects the cells DNA
When may damage to a cells DNA be seen?
With some forms of toxic injury and in tumours
What does a cell due during apoptosis?
Activates enzymes that degrade its own nuclear DNA and proteins
What happens to the membrane during apoptosis?
Membrane integrity is maintained
Is apoptosis an active or passive process?
Active- requires energy
Are lysosomal enzymes involved in apoptosis?
No
How long does apoptosis take?
It is quick- cells are gone within a few hours
How do apoptotic cells appear under the light microscope?
Shrunken
Intensely eosinophilic
Chromatin condensation, pyknosis and karyorrhexis are seen
How many cells does apoptosis affect?
Single cells, or small clusters
What do apoptotic cells show under the electron microscope?
Budding (not blebbing), which progresses to fragmentation of membrane bound apoptotic bodies
What do the fragmented membrane bound apoptotic bodies contain?
Cytoplasm, organelles and often nuclear fragments
What happens to apoptotic bodies?
They are eventually removed by macrophage phagocytosis
Does apoptosis induce inflammation?
No, because no leakage of cell contents occurs
What are the key phases of apoptosis?
Initiation
Execution
Degradation/phagocytosis
What is apoptosis triggered by?
Two key mechanisms, intrinsic and extrinsic
What do both triggering mechanisms of apoptosis culminate in?
The activation of caspases
What are caspases?
Proteases that mediate the cellular effects of apoptosis
How do caspases act?
By cleaving proteins, breaking up the cytoskeleton and initiating degradation of DNA
What does intrinsic apoptosis have as a central player?
Mitochondria
Why is intrinsic apoptosis so named?
Because all the apoptotic machinery is within the cell
What triggers intrinsic apoptosis?
Various triggers, for example DNA damage or withdrawal of growth factors or hormones
What protein is important in intrinsic apoptosis?
p53
What do the triggers for intrinsic apoptosis lead to?
Increased mitochondrial permeability, resulting in the released of cytochrome c from the mitochondria
What happens once cytochrome c has been released from the mitochondria?
It interacts with APAF1 and caspase 9 to form an apoptosome that activates downstream caspases
What is extrinsic apoptosis cause by?
External ligands, such as TRIAL and Fas, that bind to ‘death receptors’
What does binding to death receptors lead to?
Casase activation, independently of mitochondria
What happens in the degradation phase of apoptosis?
The cell breaks down into membrane bound fragments called apoptotic bodies
What do apoptotic bodies do?
Express molecules on their surface that induce phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes
What are the important apoptotic molecules?
p53 Cytochrome c, APAF1, caspase 9 Bcl-2 Death ligands Death receptors Caspases
What does p53 do?
Mediates apoptosis in response to DNA damage
What do cytochrome c, APAF1 and caspase 9 collectively form?
The apoptosome
What does Bcl-2 do?
Prevents cytochrome c release from the mitochondria, and therefore inhibits apoptosis
Give an example of a death ligand
TRAIL
Give an example of a death receptor
TRAIL-R
What happens if a cell can’t metabolise something?
It will remain within the cell
When are abnormal cellular accumulations seen?
As metabolic processes become deranged
What do abnormal cellular accumulations often seen with?
Sublethal or chronic injury
What is the outcome of abnormal cellular accumulations?
They may be reversible, and they can be harmless or toxic
What can abnormal cellular accumulations be derived from?
The cells own metabolism
The extracellular space
The outer environment
What are the main groups of intracellular accumulations?
Water and electrolytes Lipids Proteins Pigments Carbohydrates
How can fluid appear when accumulated in cells?
As discrete droplets, or diffuse waterlogging of the entire cell
What are discrete droplets of fluid in the cell called?
Vacuoles
What is the result of diffuse waterlogging of the entire cell?
Cell swelling
What is swelling due to diffuse waterlogging called?
Hydropic swelling
What is hydropic swelling due to?
Osmotic disturbance
What happens to cells in hydropic swelling?
They are enlarged, but not hypertrophic
When does hydropic swelling occur?
When energy supplies are cut off, e.g. with reduced blood supply, metabolic poisons, and sodium ions and water flood into cell
What does hydropic swelling indicate?
Severe cellular distress
What may hydropic swelling cause?
Further problems, e.g. in the brain where there is no room for expansion due to the skull
What happens as brain swelling occurs?
Blood vessels are squeezed and blood flow to the brain is reduced
What is steatosis?
The accumulation of triglycerides
Where is steatosis often seen?
In the liver
Why is steatosis often seen in the liver?
As this is the major organ of fat metabolism
What are common causes of liver steatosis?
Alcohol abuse
Diabetes mellitus
Obesity
Toxins, e.g. carbon tetrachloride
Does mild steatosis have an affect on cell function?
It doesn’t seem to
It is clinically asymptomatic
Is milk steatosis reversible?
Yes, in about 10 days if the person stops drinking alcohol
How can steatosis be diagnosed in the liver?
With the naked eye, as the liver is golden yellow rather than the usual red.
What does advanced steatosis do?
Increases the size of the organ
What is advanced steatosis the first stage of?
Alcoholic liver disease
What is the problem with cholesterol?
It cannot be broken down in the body and is insoluble
How is cholesterol eliminated?
Only though the liver
How is excess cholesterol in the cells stored?
In membrane-bound droplets
Where does cholesterol accumulate?
Within smooth muscle cells and macrophages within atherosclerotic plaques
Why does cholesterol accumulate in atherosclerotic plaques?
Perhaps because the adjacent plasma contains mcuh cholesterol
How do macrophages containing cholesterol appear microscopically?
Have a foamy cytoplasm- therefore are called foam cells
Other than atherosclerotic plaques, where is cholesterol seen?
In macrophages within the skin and tendons of people with acquired and hereditary hyperlipidaemias
What do macrophages form inpeople with acquired and hereditary hyperlipidaemias?
Small masses called xanthomas
How are proteins seen in cytoplasm?
As eosinophilic droplets or aggregates in the cytoplasm
What is Mallory’s hyaline?
A damaged protein which is seen in hepatocytes in alcoholic liver disease
What is Mallory’s hyaline due to?
Accumulation of altered keratin filaments
What kind of disorder is α1-antitrypsin deficiency?
Genetics
What happens inα1-antitrypsin deficiency?
The liver produces a version of the protein α1-antitrypsin that is incorrectly folded, and so it cannot be packaged by the endoplasmic reticulum and accumulates within this organelle and is not secreted by the liver
What does the systemic deficiency of α1-antitrypsin mean?
Proteases within the lung can act unchecked
What do patients withα1-antitrypsin deficiency develop?
Emphysema as lung tissue is broken down
What are pigments?
Coloured substances
Give an example of a pigment that is a normal cellular constituent?
Melanin
Give an example of an exogenous pigment?
Soot (carbon)
What is soot?
An urban air pollutant
What happens once soot is inhaled?
It is phagocytosed by macrophages within lung tissue (alveolar macrophages)
How is soot seen in the body?
As blackened lung tissue or as blackened peribronchial lymph nodes
What is blackened lung tissue called?
Anthracosis
Why are the peribronchial lymph nodes blackened with soot inhalation?
Because they contain macrophages which have migrated from the lungs
How long are the tissues discoloured for in soot inhalation?
For life
What is the result of soot inhalation?
It is usually harmless, however if particularly high exposure occurs, e.g. in coal miners, the lungs can become fibrotic or emphysematous- this is called coal-works pneumoconiosis
Where is the accumulation of exogenous pigments intentional?
Tattooing
What happens in tattooing?
The pigments are pricked into the skin and phagocytosed by macrophages in the dermis, which remain their indefinitely
What happens to some of the pigments from tattooing?
They will reach the draining lymph nodes and remain their (as the lymph nodes act as a filter)
Give 3 examples of endogenous pigments
Lipofuscin
Haemosiderin
Bilirubin
What is lipofuscin known as?
Age pigment, or wear and tear pigment
What colour is lipofuscin?
Brown
Where is lipofuscin found?
In ageing cells
Does lipofuscin cause injury to the cells?
No
What is lipofuscin a sign of?
Previous free radical injury and lipid peroxidation
What does lipofuscin consist of?
A polymer of oxidised, indigestible, brownish, intracellular lipids
How does lipofuscin appear under the microscope?
As yellow-brown grains within the cytoplasm
What cells is lipofuscin found it?
Long lived cells, e.g. neurones, myocardium, hepatocytes
What is haemosiderin?
An iron storage molecule
What is haemosiderin derived from?
Haemoglobin
What colour is haemosiderin?
Yellow/brown
When does haemosiderin form?
When there is a systemic or local excess of iron
What is a common example of iron overload?
Haemorrhage into tissues including the skin subcutaneous tissues, i.e. a bruise
What happens if there is a systemic overload of iron?
Haemosiderin is deposited in many organs
What is the deposition of haemosiderin into many organs called?
Haemosiderosis
Where is haemosiderosis seen?
In conditions such haemolytic anaemias, blood transfusions and hereditary haemochromatosis
What is hereditary haemochromatosis?
A genetically inherited disorder which results in increased intestinal absorption of dietary ion
Where is iron deposited in haemochromatosis?
Skin, liver, pancreas, heart and endocrine organs
What is haemochromatosis associated with?
Scarring in the liver (cirrhosis) and pancreas
What are the symptoms of haemochromatosis?
Liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas
What is the treatment for haemochromatosis?
Repeated bleeding
What is bilirubin?
A bile pigment which is bright yellow
How is bilirubin produced?
Heme is broken down in biliverdin, which is broken down to bilirubin
What does bilirubin consist of?
A stock of porphyrin rings that have broken open and lost their iron
What happens once the porphyrin has been broken?
It can never be mended, and must be eliminated in the bile
What happens when bile flow is obstructed or overwhelmed?
Bilirubin levels in the blood rise, and jaundice results
Why might bile flow be obstructed or overwhelmed?
For example with impacted gallstones, in liver disease, or haemolytic anaemias
Where can bilirubin be formed?
Anywhere in the body, not just in the liver
Why can bilirubin be formed anywhere in the body?
Because all cells contain heme as cytochromes
Where is bilirubin deposited in tissues?
Either extracellularly or intracellularly (in macrophages)
What is the problem with bilirubin deposition?
It is very toxic
Where is bilirubin taken from the tissues?
To the liver
How is bilirubin taken to the liver?
By albumin
What happens to bilirubin in the liver?
It is conjugated with glucaronic acid and excreted into the bile
What is pathological calcification?
The abnormal deposition of calcium salts within tissues
What are the two roads to pathological calcification?
One local, dystrophic calcification
One general, metastatic calcification
Which type of pathological calcification is more common?
Dystrophic
Where does dystrophic calcification occur?
In an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves, and in tuberculous lymph nodes
Is there any abnormality in calcium metabolism or serum calcium or potassium levels in dystrophic calcification?
No
What does a local change or disturbance in the tissue favour?
The nucleation of hydroxyapatite crystals
What can dystrophic calcification cause?
Organ dysfunction e.g. in atherosclerosis or calcified heart valves
Which valve never calcifies?
The pulmonary valve of the heart
Why does the pulmonary valve never calcify?
No one is sure. One theory is that the blood around the pulmonary valves is more acidic that that around the aortic valves, and the acidity prevents calcification
Where is the disturbance in metastatic calcification?
Body-wide
What happens in metastatic calcification?
Hydroxyapatite crystals are deposited in normal tissues throughout the body
When does metastatic calcification occur?
When there is hypercalcaemia secondary to disturbances in calcium metabolism
What is the effect of metastatic calcification?
It is usually asymptomatic, however it can be lethal
Can metastatic calcification regress?
Potentially, if the cause of the hypercalcaemia is corrected
What are the principal causes of hypercalcaemia?
Increased secretion of parathyroid hormone (PTH) resulting in bone resorption
Destruction bone tissue
What is a primary cause of increased secretion of PTH?
Due to parathyroid hyperplasia or tumour
What is a secondary cause of increased secretion of PTH?
Due to renal failure and the retention of phosphate
What is an ectopic cause of increased secretion of PTH?
Secretion of PTH-related protein by malignant tumours, e.g. carcinoma of the lung
What can cause destruction of bone tissue?
Primary tumours of bone marrow
Diffuse skeletal metastases
Paget’s disease of bone
Immobilisation
Give two examples of primary tumours of bone marrow
Leukaemia
Multiple myeloma
What happens in Paget’s disease of bone?
Accelerated bone turnover occurs
Why does immobilisation of bone cause destruction of bone tissue?
It removes the stimulation to bone formation whilst resorption continues
What happens as cells age?
They accumulate damage to cellular constituents and DNA.
They may also accumulate lipofuscin pigment and abnormally folded proteins.
There is a decline in their ability to replicate
What is the decline in the ability of ageing cells to replicate called?
Replicative senescence
Can cells replicate indefinitely?
No- after a certain number of divisions they reach replicative senescene
What is replicative senescence related to?
The length of chromosomes
What are the end of chromosomes?
Telomeres
What happens with every replications?
The telomere is shortened
What happens when the telomeres reach a critical length?
The cell can no longer divide
Why can germ cells and stem cells continue to divide?
They contain an enzyme called telomerase, which maintains the original length of the telomeres
Pathologically, what cells contain telomerase?
Cancer cells, so they have the ability to replicate many times
What are the major effects of excessive alcohol intake on the liver?
Fatty change
Acute alcoholic hepatitis
Cirrhosis
How does excessive alcohol intake cause fatty change?
It affects fat metabolism within the liver, resulting in steatosis
What can fatty change in the liver cause?
Hepatomegaly
Is fatty change in the liver to due alcohol consumption reversible?
Yes
What are the symptoms of fatty change in the liver?
It is generally asymptomatic
Why does acute alcoholic hepatitis occur?
As alcohol and its metabolites are directly toxic, so a binge of alcohol can result in acute hepatitis
What is seen in acute alcoholic hepatitis?
Focal hepatocyte necrosis
Formation of Mallory bodies
A neutrophilic infiltrate
What are the symptoms of acute alcoholic hepatitis?
Fever
Liver tenderness
Jaundice
Is acute alcoholic hepatitis reversible?
Usually
How many alcoholics develop cirrhosis?
10-15%
What does cirrhosis result in?
Hard, shrunken liver
How does cirrhosis appear histologically?
As micro-nodules of regenerating hepatocytes, surrounded by bands of collagen
What is the long-term outcome of cirrhosis?
It is irreversible, serious and sometimes fatal
