S1 L2 Flashcards
What is cell injury?
any disruption, physical or chemical, that results in the loss of a cell’s or tissue’s ability to maintain homeostasis
What do the degrees of cell injury depend on?
Duration of injury
Type of injury
Severity of injury
Type of tissue
What can cause cell injury?
Hypoxia
Toxins
Physical agents: direct trauma, extreme of temp, pressure changes, electrical currents
Radiation
Microorganisms
Immune mechanisms =acute and chronic inflammation, hypersensitivity, autoimmune reactions.
Dietary insufficiency and deficiencies, dietary excess
Genetic abnormalities – inborn errors of cell function, autoimmunity.
What is hypoxia?
Oxygen deprivation
What is ischaemia?
Loss of oxygen and other substrates= more rapid and severe cell injury
What are the causes of hypoxia?
Hypoaxemic
Anaemic
Ischaemic
Histiocytic
What is hypoxaemic hypoxia?
Arterial content of oxygen is low =the oxygen pressure in the blood being too low to saturate haemoglobin
Reduced inspired pO2 altitude
Reduced absorption secondary to lung disease
What is anaemic hypoxia?
Decreased ability of haemoglobin to carry oxygen
=anaemia or CO poisoning
What is ischaemic hypoxia?
Interruption of blood supply
Blockage of a vessel or heart failure
What is histiocytic hypoxia?
Inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
E.g. cyanide poisoning
What things are toxic?
Glucose and salt in hypertonic solutions High conc of O2 Poisons Pollutants Insecticides Herbicides Absbetos Alcohol Narcotic drugs Medicines
How does the immune system damage the body’s cells?
Hypersensitivity reactions host tissue is injured secondary to overly vigorous immune reaction
Autoimmune reactions- immune system fails to distinguish self from non-self
Which cell component are most susceptible to injury?
Cell membranes inc organellar membranes
Nucleus- DNA
Proteins- Enzymes
Mitochondria- oxidative phosphorylation
What happens at the molecular level in hypoxia?
Blood vessel is occulded
Deprives tissue of oxygen
Mitochondrial ATP production stops
Decreased ATP
NA-K pump decreases in activity= influx of Ca2+, H2O, Na, effluent of K+= cellular swelling, loss of Microvilli, bless, ER swelling
In the absence of oxygen, the cell will carry put anaerobic respiration to provide ATP.
Increase of glycolysis = increase in lactic acid = decrease in pH and glycogen = clumping of nuclear chromatin
Detachment of ribosomes- decrease protein synthesis = lipid deposition
The cell will initiate a stress (heat-shock) response to repair damage.
What happens in prolonged hypoxia?
Increased cytotoxic calcium enters the cell due to the failure of the Na+/Ca2+ exchanger and activates multiple enzymes= irreversible cell injury resulting in cell death. These enzymes and their effects:
Phospholipase- Destruction of the cell membrane
Proteases- Damage membrane proteins and the cell cytoskeleton
ATPase- Further loss of ATP
Endonucleases-Cleavage of the DNA backbone and clumping of nuclear chromatin
The cellular organelles will then begin to swell, enzymes will be released and damage other cellular components, and the damaged cell membrane begins to bleb
What happens after cell death?
release many of its intracellular molecules (such as potassium, cell specific enzymes, myoglobin) into the surrounding tissue= general toxic effects on the neighbouring cells and cause local irritation and inflammation.
Different cell types have different molecules, and so levels of these molecules in blood tests can be useful for diagnosis
What are free radicals?
Single unpaired electron in outer orbit
Unstable configuration= reaction with other molecules
Name three free radicals that are of biological significance in cells.
Hydroxyl (OH)
Superoxide (O2)
Hydrogen peroxide (H2O2)
How are free radicals produced?
Normal metabolic reactions
Inflammation: respiratory burst
Radiation
Contact with unbound metals in body: Fe in Fenton reaction and Cu
Drugs and chemicals: liver metabolism of paracetamol or carbon tetrachloride by P450 system
How do free radicals injure cells?
Causes oxidative imbalance
Target lipids in cell membrane= lipid peroxidation causing further formation of free radicals
Oxidised proteins, carbs, DNA= form cross links, bend out of shape, break, mutagentic
How does the body control free radicals?
Anti-oxidant scavengers: donate electrons to the free radical- vitamins A, C, E
Metal carrier and storage proteins (transferring, ceruloplasmin): sequester iron and copper
Enzymes neutralise free radicals: superoxide dismutase, catalase, glutathione peroxidase
How can cell protect itself against injury?
Heat shock proteins= mend misfiled proteins and maintain cell viability
Unfoldases or chaperonins
What does a hypoxic cell look like under a microscope?
Cytoplasmic changes
Nuclear changes
Abnormal cellular accumulations
What changes can we see in a cell undergoing reversible injury?
Blebs Generalised swelling Clumping of nuclear chromatin Autophagy by lysosomes ER swelling Dispersion of ribosomes Mitochondrial swelling
What can we see under a microscope of irreversible injury?
Rupture of lysosomes and autolysis Nucleus: pyknosis, karyolysis, karyorrhexis Defects in cell membrane Myelin figures ER lysis
Describe the nuclear changes seen in irreversible cell injury
Pyknosis-Irreversible condensation of chromatin and nuclear shrinkage.
Karyolysis-Dissolution of the nucleus.
Karryorrhexis-Destructive fragmentation of the nucleus.
What are abnormal cellular accumulations?
When metabolic processes become deranged
Occurs with sublethal or chronic injury
Can be reversible, harmless or toxic
Can derive from: cell’s own metabolism, extracellular space, outer environment
What are the main five groups of intracellular accumulations?
Water and electrolytes Lipids Carbohydrates Proteins Pigments
When does fluid accumulate in the cells?
Hydropic swelling When energy supplies cut off Severe cellular distress Na and water flood into cell Problem in brain
When do lipids accumulate in the cell?
Steatosis- acculturation of triglycerides in liver
Asymptomatic if mild
What are the causes of steatosis?
Alcohol
Diabetes mellitus
Obesity
Toxins
How does cholesterol accumulate in the body?
Excess sorted in cells in vesicles
Accumulates in smooth muscle cells and macrophages in atherosclerotic plaques = foam cells
Present in macrophages in skin and tendons of people with hereditary hyperlipidaemias=xanthomas
How do proteins accumulate in the cells?
Eosinophilic droplets or aggregates in the cytoplasm
Seen in alcoholic liver disease: Mallory’s hyaline (damaged keratin filaments)
How is protein accumulation seen in 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
When do pigments accumulate in cells?
Carbon/coal dust/soot-urban air pollutant is inhaled and phagocytosis by alveolar macrophages
Anthracosis and blackened peribronchial lymph nodes
Usually harmless unless in large amounts = fibrosis and emphysema
How do tattoos get into skin?
Pigment pricked into skin and phagocytosed by macrophages in dermis – remains there
Some pigment reaches draining lymph nodes
What is haemosiderin?
Iron storage molecule
Derived from haemoglobin, yellow/brown
Forms when there is a systemic of local excess of iron e.g. 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 haemochromatosis?
Increased intestinal absorption of dietary iron
Iron deposited in skin, liver, pancreas, heart and endocrine organs
What are the symptoms of hereditary haemochromatosis?
Liver damage
Heart dysfunction
Multiple endocrine failures esp of pancreas
What is the treatment of haemochromatosis?
Repeated bleeding
What is accumulating in jaundice?
Accumulation of bilirubin
Bile flow obstructed or overwhelmed, bilirubin in blood rises and jaundice results
Deposited in tissues extra cellular lay or in macrophages
What happens when membranes are leaky?
Cause local inflammation
General toxic effects on body
May appear in high concentrations in blood and can aid in diagnosis
What important things leak out of a cell?
Myoglobin
Enzymes
Potassium
What happens when tissues are calcified?
Abnormal deposition of calcium salts within tissues
Can be localised (dystrophic) or generalised (metastatic)
Dystrophic is more common- occurs in an area of dying tissue, atherosclerotic plaques, aging or damaged heart valves, in tuberculous lymph nodes, some malignancies
Describe metastatic calcification
Systemic and occurs throughout the body
hypercalcaemia due to abnormal calcium metabolism, resulting in hydroxyapatite crystals being deposited in tissues.
Usually symptomless but, in some cases, can pose a serious risk to health
What are the causes of dystrophic calcification?
Local change/disturbance favours nucleation of hydroxyapatite crystals
Can cause organ dysfunction e.g. atherosclerosis, calcified heart valve
What causes hypercalecaemia?
Increased secretion of PTH resulting in bone resorption
Destruction of bone tissue e.g. tumours, accelerated bone turnover, immobilisation
What is oncosis?
Cell death with swelling, characterised by ATP depletion.
What is necrosis?
Described the morphological changes that occur after a cell has died (this is not a process, but an appearance).
What are the two main types of necrosis?
Coagulative- protein denaturation e.g. ischaemia of solid organs
Liquefactive (colliquitive) enzyme release e.g. ischaemia in loose tissues; presence of many neutrophils
What does coagulative necrosis look like?
Occurs in solid organs such as the liver
Denaturation of protein dominates over release of active proteases
Cellular architecture is preserved e.g ghost outline of cells
What does liquefactive necrosis look like?
Happens in loose and soft tissues such as the lungs and the brain
Enzyme degradation is substantially greater than denaturation
Leads to enzymatic digestion of tissues
What is caseous necrosis?
Associated with infections esp TB
A form of cell death in which the tissue has a cheese-like appearance, seen under the microscope as a mix of coagulative and liquifactive states.
Contains amorphous (structureless) debris
What is fat necrosis and what does it look like?
characterized by the action of digestive enzymes on fat released from adipocytes. In fat necrosis the enzyme lipase releases fatty acids from triglycerides. The fatty acids then complex with calcium to form soaps. These soaps appear as white chalky deposits.
What is gangrene?
Necrosis visible to the naked eye
What is infarction?
Necrosis caused by reduction in arterial blood flow
Can result in gangrene
What is infarct?
An area of necrotic tissue which is the result of loss of arterial blood supply- an area ischaemia necrosis
What is dry gangrene?
Necrosis modified by exposure to air- coagulative necrosis
What is wet gangrene?
Necrosis modified by infection- liquefactive necrosis
What is gas gangrene?
Wet gangrene where the infection is with anaerobic bacteria that produce gas
What are the commonest causes of infarction?
Thrombosis
Embolism
Why are some infarcts white?
=anaemic infarcts
Occlusion of an end artery
Often wedge-shaped
Coagulative necrosis
Why are some infarcts red?
=haemorrhagic infarct Loose tissue Dual blood supply Numerous anastomoses Prior congestion Raised venous pressure Re-perfusion
What is the consequence of infarction?
Can range from none to death
What does the consequence of infarction depend on?
Alternative blood supply
Speed of ischaemia
Tissue involved
Oxygen content of the blood
What is ischaemia-reperfusion injury?
If blood blow is returned to the damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow hadn’t been returned
What are the causes of ischaemia- reperfusion?
Increased production of oxygen free radicals with reoxygenation
Increased number of neutrophils resulting in more inflammation and increased tissue injury
Delivery of complement proteins and activation of the complement pathway
What is apoptosis?
Cell death with shrinking which occurs as a normal and controlled part of the growth and development of an organism.
When does apoptosis occur physiologically?
In order to maintain a steady state
Hormone-controlled involution
Embryogenesis- stain for apoptotic cells in the developing paw of a foetal mouse
When does apoptosis occur pathologically?
Cytotoxic T cell killing of virus-infected or neoplasticism cells
Cell DNA is damaged- non-random, internucelosomal cleavage of DNA
Graft rests host disease
What are the three phases of apoptosis?
Initiation- triggered by intrinsic or extrinsic factors
Execution- Activation of caspases which cause cleavage of DNA and proteins in the cytoskeleton.
Degradation and phagocytosis- The cell shrinks and splits into small apoptotic bodies containing organelles. These are engulfed by neighbouring cells
How is apoptosis triggered?
Intrinsic and extrinsic mechanisms that activate caspases
What are caspases?
Enzymes that control and mediate apoptosis
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 proteins is activated= outer mitochondrial membrane becoming leaky
Cytochrome C is released from mitochondria = activation of capases
How is the extrinsic pathway initiated and carried out?
Initiated by extracellular signals
Triggers: cells that are in danger e.g. tumour cells, virus-infected cells
TNFa secreted by T killer cells= binds to cell receptor =death receptor
Causes activation of capases
How are apoptotic bodies phagocytosed?
Both intrinsic and extrinsic pathways cause the cells to shrink and break up into apoptotic bodies
Apoptotic bodies express proteins on their surface= recognised by phagocytes or neighbouring cells
Degradation takes place within the phagocyte/neighbour
Compare apoptosis and necrosis
Apoptosis
Shrinkage and chromatin condensation
Budding
Apoptotic bodies phagocytosed with no inflammation
Necrosis
Swelling
Blebbing with disruption of cell membrane
Release of proteolytic enzymes with important inflammatory reaction
Can cells live forever?
As cells age, they accumulate damage over time Hayflick limit (around 50 times a cell can divide). a cell can no longer replicate= replicative senescence telomeres become shorted with each cell division= once at a critical length- cell with undergo apoptosis
