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