Cell Injury Flashcards
What does the degree of cell injury depend on?
The degree of injury depends on:
- Type of Injury
- Severity of injury
- Type of tissue
What things can cause cell injury?
Hypoxia (lack of oxygen)
Toxins
Physical agents
- Direct trauma
- Extremes of temperature
- Changes in pressure
- Electric currents
Radiation
Micro-organism
Immune mechanisms
Dietary insufficiency and deficiency, dietary excess
What is the difference between Hypoxia and Ischaemia?
Hypoxia - Lack of oxygen
Ischemia - Lack of blood supply. This is more severe because it means that cells lack nutrients as well as oxygen.
What are the causes of hypoxia?
Hypoxaemic Hypoxia-
This is when the arterial content of oxygen is low.
It occurs when there is reduced inspired oxygen at high altitude or when there is reduced absorption because of lung disease.
Anaemia Hypoxia- This is the decreased ability of haemoglobin to carry oxygen.
This occurs because of either anaemia or carbon monoxide poisoning.
Ischaemic Hypoxia-
This is when there is interruption to the blood supply.
It occurs when there is blockage of a vessel or heart failure.
Histiocytic hypoxia-
This is the inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes.
This occurs in cyanide poisoning.
How does the immune system damage the body’s cells?
Hypersensitivity reactions - Host tissue is injured secondary to an overly vigorous immune reaction eg urticaria (hives).
Autoimmune reactions - immune system fails to distinguish self from non-self e.g. Grave’s disease of thyroid.
Which cell components are most susceptible to injury?
Cell membrane - inc. the Plasma membrane and the organelle membranes.
Nucleus - inc. DNA.
Proteins - inc. structural proteins and enzymes.
Mitochondria - Oxidative Phosphorylation.
What is happening at the molecular level in hypoxia?
Firstly, it causes a decrease in the rate of oxidative phosphorylation on the mitochondria.
This causes the level of ATP to drop (5-10% of normal)
NaKATPase can no longer work
This causes an influx of Ca2+ H2O and Na+ and an efflux of K+
This results in cellular swelling, loss of microvilli, Blebs, ER swelling and Myelin Figures.
The lack of ATP also means that the rate of glycolysis (anaerobic resp) increases.
This causes a drop in pH which results in clumping of nuclear chromatin.
The increased rate of glycolysis also means there there is a decresed supply of glycogen.
Also, ribosomes drift from ER so the rate of protein synthesis decreases. This results in lipid deposition.
Deposition of substances cell cant metabolise (All above reversible)
What occurs in prolonged hypoxia?
Ca makes it irreversible
It activates:
- ATPase to cause a further decrease in ATP.
- Phospholipases which cause a decrease in phospholipids.
- Proteases. These disrupt the membrane and cytoskeleton of proteins.
- Endonuceases which result in damage to nuclear chromatin.
What occurs in cell injury with causes other than hypoxia?
The sequence of events for other insults may be different but as the cell has limited responses to injury, but the outcomes are often similar.
Other forms of injustice might attack different key sturctures initially. eg extreme cold (frostbite) initially damages cell membranes.
Free radicals also primarily damage cell membranes.
What are free radicals?
A reactive oxygen species.
A single, unpaired e- in an outer orbit. This is an unstable configuration so they react with other molecules and often produce other free radicals.
What 3 free radicals are of particular biological significance in cells?
OH. (hydroxyl) -The most dangerous
O2- (superoxide)
H2O2 (hydrogen peroxide)
When are free radicals produced?
- Normal metabolic reactions e.g. oxidative phosphorylation
- Inflammation: Oxidative burst of neutrophils
- Radiation: H2O = OH.
- Contact with unbound metals within the body: Iron (By Fenton reaction) and Coppper. (Free radical damage occurs in haemochromatosis and Wilson’s disease.)
- Drugs and chemicals: e.g. in the liver during metabolism of paracetamol or CCl4 by P450 system.
How does the body control free radicals?
- Anti-oxidant scavengers: Donate e- to the free radicals (Vitamins A, C and E).
- Metal carrier and storage proteins (transferrin, ceruloplasmin): sequester iron and copper.
- Enzymes that neutralise free radicals.
- Superoxide dismutase
- Catalase
- Glutathione peroxidase
How do free radicals injure cells?
If the number of free radicals overwhelms the anti-oxidant system = oxidative imbalance.
The most important targets are lipids in cell membranes. These cause lipid peroxidation which leads to the generation of further free radicals (an autocatalytic chain reaction).
Free radicals can also oxidise proteins, carbohydrates and DNA. These molecules become bent out of shape, broken or cross linked, This means they are now mutagenic and therefore carcinogenic.
How else can the cell protect itself against injury?
Heat shock proteins.
In cell injury, heat shock aims to ‘mend’ mis-folded proteins and maintain cell viability.
These are called unfoldases or chaperonins Eg Ubiquitin.
What do injured and dying cells look like under a microscope?
In Hypoxia:
Swelling
Cytoplasmic changes - cells become darker
Nuclear changes - Pyknosis (condesation if chromatin), Karyorrhexis (the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm), karyolysis (dissolution of a cell nucleus).
Abnormal Cellular accumulation
Whay do you see under an electron microscope in reversible cell damage?
What would you see under an electron microscope in irreversible cell injury?
Define oncosis
Cell death with swelling, the spectrum of changes that occur in injured cells prior to death. (Some textbooks describe this process as necrosis)
Define Necrosis
In a living organism the morphological changes that occur after a cell has been dead some time. (See after 12-24 hours).
What are the two main types and the two special types of necrosis?
Main:
Coagualative
Liquefactive (Colliquitive)
Special:
Caseous
Fat necrosis
What is the difference between coagulative and liquefactive neurosis?
Coagulation - Protein denaturation rather than liquefaction. Denaturation dominates over the release of active proteases. The cellular architecture is somewhat preserved. There is a “ghost outline” of cells.
e.g. Ischaemia of solid organs.
Liquefactive necrosis- Enzyme release. Enzyme degradation is substantially greater than denaturation. This leads to enzymatic digestion (liquefaction) of tissues.
e.g. Ischaemia in loose tissues; presence of many neutrophils.
What is caseous necrosis?
Caseous neurosis contains amorphous (sturctureless) debris. It is particualrly assosiated with infections, especially TB.
Caseum means cheese in Latin bevause, with the naked eye, it was thought to look like cheese.
What is fat necrosis and what does it look like?
Fat neucrosis is a hard firm lump which can feel similar to a tumour. It is often see, when patients acute pancreatitis
Define gagrene
Necrosis visible to the naked eye - an appearance of necrosis
Define Infarction
Necrosis caused by reduction in arterial blood flow.
Infarction is a cause of necrosis and can result in gangrene.
Define infarct
An area of neucrotic tissue which is the resutl of a loss of arterial blood supply.
It is an area of ischaemic neucrosis.
What is the difference between dry and wet gangrene?
Dry gangrene = necrosis modified by exposure to air (coagulative necrosis)
Wet gangrene = necrosis modified by infection (liquefactive necrosis)
What is gas gangrene?
Wet gangrene where the infection is with anaerobic bacteria that produces gas. Common in motorcycle accidents. Was a death sentence before antibiotics were invented.
What are the most common causes of infarction?
Thrombosis - the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system
Embolism - When thrombus travels in blood supply and blocks different blood vessel. An embolism can also be caused by fat globules, gas / air or foreign material.
How else can tissues become infarcted?
Hernia
Testicular Torsion
Bowel Infarction
What does an infarcted tissue look like?
Why are some infarcts white?
=Anaemic infarcts
These occur in ‘Solid organs’ (dense tissue) or occlusions of an end artery (with a single blood supply).
They are often wedge shaped
Coagulation necrosis
e.g. Myocardium, Kidney, Spleen
Why are some infarction red?
= Haemorragic infarct
Loose tissue
Dual blood supply
Numerous anastomoses (connections to other sturctures)
Prior congestion
Raised venous pressure
Re-perfusion
What is the consequence of infarction?
Anything from none to death.
It depends on:
Alternative blood supply
Speed of ischaemia
Tissue involved
Oxygen content of the blood ( more likely to get infarction if anaemic)
What is ischaemia-reperfusion injury?
It is the tissue damage caused when blood supply returns to tissue (re- + perfusion) after a period of ischemia or lack of oxygen (anoxia or hypoxia).
Paradoxically, if blood flow is returned to a damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow hasn’t been returned.
What are the possible causes of ischaemia-reperfusion injury?
- Increased porduction of oxygen free radicals with reoxygenation.
- Increased number of neutrophils resulting in more inflamation and increased tissue injury.
- Delivery of complement proteins and activation of the complement pathway.
When membranes are leaky, what are the consequences of molecules leaking out?
They can have both local and systemic effects.
- Can cause local Inflamation
- May have general toxic effects on the body
- May apppear in high conc in the blood and can aid diagnosis
What important molecules leak out during neucrosis?
- Potassium eg lots in burns and can stop heart or in tumour lysis syndrome.
- Enzymes eg AST or CK to diagnose myocardial infarction. Or amylase for acute pancreatitis.
- Myoglobin - Out of skeletal muscle when significant damage has occured.
Define apoptosis
Cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins.
Why does apoptosis have a characteristic microscopic appearance?
Because there is characteristic DNA breakdown. Non-Random, internucleosomal clevage of DNA (in oncosis DNA is chopped into pieces of random length).
What are some characteristic of apoptosis?
Active
Equal and opposite force to mitosis
Enzymes activated that degrade nuclear DNA and proteins
Membrane integrity is maintained
Lysosomal enzymes are not involved
It is quick, the cells are gone in a few hours
It can be pathological or physiological
When does apoptosis occur physiologically?
- In order to maintain a steady state
- Hormone controlled involution
- Embryogenesis
When does apoptosis occur pathologically?
- Cytotoxic T cells killing virus-infected or neoplastic cells
- When cells are damaged particularly with damaged DNA
- Graft vs host disease
What does apoptosis look like?
DNA cleaved in same way
DNA clumps under nuclear membrane
Shrinks further and begins to fragment
Breaks up into apoptitic bodies
Buds instead of blebs (in oncosis)
How does apoptosis occur?
Apoptosis occurs in three phases:
Initiation
Execution
Degradation and phagocytosis
What hapeens in the initiation and execution phases of apoptosis?
This are triggered by two mechanism -intrinsic and extrinsic
Both result in activation of caspases. These are enzymes that control and mediate apoptosis. They cause cleavage of DNA and proteins of the cytoskeleton.
How is the intrinsic pathway initiated and carried out?
Initiating signal comes from within the cell.
Triggers:
- Most commonly irreparable DNA damage
- Withdrawal of growth factors or hormones
p53 protein is activated and this results in the outer mitochondrial membrane becoming leaky.
Cytochrome C is released from the mitochondria which causes the activation of caspases.
How is the extrinsic pathway initiated and carried out?
Initiated by extracellular signals
It is triggered by cells that are a danger eg tumour cells and virus infected cells.
One of the signals is TNF-a
- This is secreted by killer T cells.
- It binds to the cell membrane receptor (the death receptor)
- It results in the activation of caspases
Why are the apoptosis bodies phagocytosed?
Both intrinsic and extrinsic pathways cause the cells to shrink and break up into apoptotic bodies.
The apoptotic bodies express proteins on their surface.
They can now be recognised by phagicytes or neibouring cells.
Finally degredation takes place within the phagocyte / neighbour.
Compare the structural changes in oncosis and apoptosis
Where do abnormal cellular accumulations come from?
They are seen when abnormal processes become deranged
Often occur with sublethal or chronic injury
Can be reversible
Can derive from:
- cell’s own metabolism
- extracellular space eg spilled blood
- the outer environment eg dust
What are the five main things that accumulate in cells?
Water and electrolytes
Lipids
Carbohydrates
Proteins
Pigments
When does fluid accumulate in cells?
Hydropic swelling
Occurs when energy supplies are cut off eg hypoxia
indicates severe cellular distress
Na+ and water flood into cell
Where is fluid accumulation a big problem?
The brain.
This is because it is in a fixed cavity.
Death because of cerebral oedema
When do lipids accumulate in cells?
Alcohol
Diabetes
Obesity
Toxins
What is another name for lipid accumulation? Where is this often seen?
Steatosis (accumulation of triglycerides)
Often seen in liver because it is a major organ of fat metabolism
If the steatosis is mild then it may be asymptomatic
Where does excess cholestrol acculumulate?
Cholesterol:
- cannot be broken down and is insoluble.
- Can only be eliminated through the liver.
- Excess is stored in vesicles.
- It accumulates in smooth muscle cells and macrophages in athlerosclerotic plaques (foam cells)
- It is also present in macrophages in skin and tendons of people with hyperlipidaemias = xanthomas.
In what conditions do proteins accumulate in cells?
Seen as eosinophilic droplets or aggregations in the cytoplasm.
Alcoholic liver disease:
–Mallorys hyaline (damaged keratin filaments)
a1-antitrypsin deficiency:
–Liver produces incorrectly folded a1-antitrypsin protein (a protease inhibitor)
–Cannot be packaged by ER, accumulates within ER and is not secreted
–Systemic deficiency - proteases in lung act unchecked resulting in emphysema
What pigments acculumulate in cells? How?
Carbon/coal dust/ soot - urban air pollution
Inhaled and phagocytosed by alveolar macrophages
Anthracosis and blackened peribronchial lymph nodes
Usually harmless, unless in large amounts = fibrosis and emphysema = coal worker’s pneumoconiosis
Tattooing
pigments pricked into skin
Phagocytosed by macrophages in dermis and remain there
Some pigment will drain to lymph nodes
What is haemosiderin and when does it accumulate in cells?
Haemosiderin:
Ion storage molecule
Derived form haemoglobin, yellow / brown
Forms when there is systemic or local excess of iron e.g. a bruise
With systemic overload of iron, haemosiderin is deposited in many organs = haemosiderosis
Seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis
What is hereditary haemachromatosis?
Genetically inherited disorder - results in increased intestinal absorption of dietary iron.
Iron is deposited in skin, liver, pancreas, heart and endocrine organs -often associated wiht scarring in liver (cirrhosis) and pancreas.
Symptoms include liver damage, heart dysfunction and multiple endocrine failiures, especially of the pancreas.
It was called “bronze diabetes’
Treatment is repeated bleeding (giving blood once per month)
What is accumulated in Jaundice?
Bilirubin - a bright yellow pigment.
Where and how is bilirubin formed?
Bilirubin is produced because of the breakdown of heme, stacks of broken porphyrin rings.
It is formed in all cells of the body (cytochromes contain heme) but must be eliminated in bile (which is synthesised by the liver).
It is taken from tissues by albumin to the liver, then conjugated with bilirubin and excreted in bile.
If bile flow is obstructed or overwhelmed, bilirubin in the blood rises and jaundice results.
It is then deposited in tissues extracellularly or in macrophages.
What are the mechanisms of intracellular accumulations?
Abnormal metabolism
Alterations in protein folding and transport
Deficiencies of critical enzymes
Inability to degrade phagocytosed particles
What is the calcification of tissues?
This is the abnormal deposition of calcium salts within tissues.
What are the two types of calcification? Which is most common?
Localised / Dystrophic or generalosed / metastatic.
Dystrophic is much more common. It occurs in areas of dying tissuem athlerosclerotic plaques, aging or damaged heart valves( on left side of the heart), in tuberculus lymph nodes and some malignancies.
Why does dystrophic calcification occur?
No abnormality in calcium metabolism, or serum calcium or phosphate concentrations.
There is a local change in the tissue which favours the nucleation of hydroxyapatite crystals .
Can cause organ dysfunction e.g. athlesclerosis or calcified heart valves
Why does metastatic calcificatiom occur?
It occurs due to hypercalcaemia secondary to disturbances in calcium metabolism.
Hydroxyapatite crystals are deposited in normal tissues throughout the body.
Usually asymptomatic but it can be lethal.
Can regress if the cause of hypercalcaemia is corrected.
What causes hypercalcaemia?
Increased secretion of parathyroid hormone resulting in bone resorbtion:
Primary - due to parathyroid hyperplasia or tumour
Secondary - due to renal failiure and the retention fo phosphate
Ectopic - secretion of PTH-related protein by malignant tumours (e.g. carcinomas of the lung)
Destruction of bone tissue:
Primary tumours of bone marrow e.g. leukaemia, multiple myeloma
Diffuse skeletal metastases
Paget’s disease of bone - when accelarated bone turnover occurs
Immobilisation
Can cells live forever?
Yes and No.
No! As cells age, they accumulate damage to their cellular constituents and DNA. After a certain number of decisions they reach replicated senescence - relate to length of chromosomes. This occurs when telomeres reach a critical length (They shorten with every cell division).
Yes! Germ cells and stem cells contain telomerase. This is an enzyme that maintains the origional length of the telomeres so that they can continue to replicate.
But, many cancer cells produce telomerase so they can replicate multiple times.
