Session 1 -> Cell injury Flashcards
Name some toxins which can cause cell injury
- High O2
- Narcotics
- Pesticides
- Glucose
Name some physical agents of cell injury
- Trauma
- Heat
- Cold
- Radiation
Name some chemical agents which can cause cell injury
- Alcohol
- Therapeutic drugs
- Poisons
What are the two immune mechanisms of cell injury?
- Hypersensitivity
- Autoimmune
How does hypersensitivity cause cell injury?
-An overly vigorous immune reaction ensues which injures cells
List the frequent targets of cell injury
- Cell membranes
- Nucleus
- Proteins
- Mitochondria
To what organelle in particular is membrane damage dangerous and why?
- Lysosomes
- Leakage of contents -> contains hydrolases etc would damage cell
What is the main reason why damage to the mitochondria causes cell injury?
-Mitochondria cannot carry out oxidative phosphorylation -> no ATP produced
What is hypoxia?
-Oxygen deprivation
What is the first consequence of oxygen deprivation?
-Decreased aerobic respiration
Name a cell type which can tolerate hours of hypoxia
-Dermal fibroblasts
Is hypoxia reversible or irreversible?
-Both, initially reversible but cell injury passes a point of no return
What is the main consequence of decreased aerobic respiration (oxidative phosphorylation)?
-Decreased ATP levels
At what level of decreased ATP does cellular function become compromised?
-When levels reach 5-10%
What happens to lipid and protein in reversible hypoxia?
-Accumulates within the cell as there is no ATP for metabolism
What happens to the glycogen stores in reversible hypoxia?
-They are used up
Why is protein synthesis decreased during reversible hypoxia?
-Ribosomes fall off the rER as energy is required to anchor them there
Why does cell swelling (oncosis) occur during hypoxia?
- NaK pump fails as this requires ATP
- K+ leaves the cell down its concentration gradient
- Na+ enters down its concentration gradient
- Ca2+ enters and the imbalance of electrolytes draws in water causing swelling
Why does loss of microvilli, blebbing and myelin figure appearance occur in hypoxia?
-Due to the imbalance of electrolytes
Why does lactic acidosis occur in hypoxia?
-Anaerobic respiration takes over resulting in a build up of lactate
Why does enzyme denaturation occur in hypoxia?
-Due to the lactic acidosis
Why does clumping of nuclear chromatin occur in hypoxia?
-Due to the decrease in pH caused by anaerobic respiration causing a build up of lactate
What is the main factor which causes hypoxia to become irreversible?
-The cell membrane becomes increasingly permeable causing a further increase in the influx of Ca which is toxic to the cell
What is the result the of increasing intracellular calcium during irreversible hypoxia?
-There is increased activation of cellular enzymes, including ATPases, phospholipases, proteases and endonucleases
What is the consequence of activation of ATPases during irreversible hypoxia?
-The enzymes further reduce the levels of available ATP within the cell
What is the consequence of the activation of phospholipases in irreversible hypoxia?
-hydorlyses phospholipids in cell membrane, further adding to the membrane damage
What is the consequence of activation of proteases during irreversible hypoxia?
-Further increase the breakdown of membranes and cytoskeletal proteins
What is the consequence of activation of endonucleases during irreversible hypoxia?
-DNA becomes irreparably damaged
What are the four groups of causes of hypoxia?
- Hypoxaemic
- Anaemic
- Ischaemic
- Histiocytic
What is hypoxaemic hypoxia? Give an example
- hypoxia causes by low arterial pO2
- altitude
- hypoxia secondary to lung disease
What is anaemic hypoxia? Give an example
- Hypoxia caused by the decreased ability of Hb to carry oxygen
- CO poisoning
- Anaemia
What is ischaemic hypoxia? Give an example
- Hypoxia caused by the interruption of a blood supply
- Heart failure
- Occlusion
What is histiocytic hypoxia? Give an example
- Hypoxia caused by the inability of the tissues to utilise oxygen
- Cyanide poisoning (inhibits cytochrome system)
Define ischaemia
-Inadequate flow of blood to part of the body caused by constriction or blockage of the blood vessel supplying it
What may cause there to be a decreased arterial supply?
- Occlusion
- Low BP
- Reduced venous drainage
Why is cell injury caused by ischaemia more rapid and severe than hypoxia?
-There is reduced metabolic substrates as well as a reduced oxygen supply
When does ischaemic reperfusion injury occur?
-When bloodflow is re-established to damaged tissue which has not yet become necrotic
How can reperfusion of tissue be dangerous?
- The returning bloodflow causes an increase in superoxide radical production
- Increased neutrophils which illicit an increased inflammatory response
- Blood contains complement factors which are activated leading to further damage from inflammatin
What is the main target of free radicals?
-Cell membranes
Why are free radicals dangerous?
-They are very unstable, highly reactive molecules which react with other stable molecules, often producing a chain reaction involving the production of more free radicals
What are the three main free radicals in the body?
- OH•
- O2•
- H2O2
How is O2• produced by radiation?
-Directly lyses water
What is the fenton reaction?
-The reaction of H2O2 with Fe to produce O2•
When does the fenton reaction become significant?
-During bleeding as this provides a free source of Fe which can be used
Why is the haber-weiss reaction useful?
-Although it produces -OH•, it uses O2•
What overdose causes death by liver failure due to reactive oxidative species production?
-Paracetamol
What is lipid peroxidation?
-The reaction of lipids with free radicals to generate a lipid peroxide
Where are the lipids, which are targeted in lipid peroxidation usually located?
-In cell membranes
Why is lipid peroxidation so dangerous?
-It is an autocatalytic chain reaction
What are the three main mechanisms of free radical removal?
- Enzymes (SOD)
- Vitamins (ACE)
- Storage proteins (copper/iron)
What is the function of heat shock proteins during cell injury?
-To locate and repair mis-folded proteins in order to maintain cell vibility
What happens to protein/hsp production during cell injury
- Protein production decreased
- HSP production increased
How do reversibly injured cells appear under a light microscope?
- Swollen
- Cytoplasm is reduced in pink (accumulation of water)
- Pyknosis
What is pyknosis?
-Chromosome clumping
How does irreversible cell injury appear under a light microscope?
- Karryohexis
- Karyolysis
What is karryohexis?
-Chromosomal lysis
What is karyolysis?
-Cell disintergration
How do reversibly injured cells appear under an electron microscope?
- Swollen
- Pyknosis
- Autophagy
- ER swelling
- Blebbing
What is blebbing?
-Bumps on the membrane surface when the cytoskeleton has detached
How does an irrervsibly injured cell appear under an electron microscope?
- Karryohexis
- Karyolysis
- ER Lysis
- Lysosomal lysis
- Mitochondrial swelling
- Accumulation of denatured proteins
Define oncosis
-Cell death with swelling
What types of cell injury is oncosis typically associated with?
- Hypoxia
- Anaemia
Why does swelling occur in oncosis?
-Due to changes in ionic gradients drawing water in
What is necrosis?
-The morphological changes which occur after cell death (4-24hrs)
What happens to the plasma membrane during necrosis?
-Ruptures
What other process is often seen alongside necrosis?
-Inflammation
Do cells swell of shrink in necrosis?
-Swell
What are the 4 types of necrosis?
- Coagulative
- Liquefactive
- Caseous
- Fat necrosis
What happens to the proteins in coagulative necrosis?
-They undergo denaturation rather than degredation resulting in protein clumping
With what type of cell injury is coagulative necrosis often seen?
-Ischaemia
How does coagulative necrosis appear to the naked eye?
-Firm and white
Why does coagulative necrosis stain intensely pink?
-Due to extensive protein denaturation
Why is coagulative necrosis said to have a ghost outline?
-The architecture of the cells is preserved
What happens to the proteins in liquefactive necrosis?
-Proteins are autolysed and dissolved as protein degrdation > protein denaturation
How does liquefactive necrosis appear to the naked eye?
-The dead tissue liquefies
Why does the dead tissue liquify?
-Due to enzymatic digestion of the tissue
Liquefactive necrosis is often associated with what other process?
-Inflammation
Where does liquefactive necrosis often occur?
- Areas of soft tissue with low supporting cells eg brain
- Abscesses
- Infections
What does excessive neutrophil infiltrate lead to in liquefactive necrosis?
-Purulent pus in exudate
When does caseous necrosis occur?
- Often during infections such as TB
- Associated with granulomatous inflammation
What does caseous necrosis appear like to the naked eye?
-Cheese-like
What similarity does caseous necrosis share with coagulative necrosis?
-The cells retain there architecture leaving a ghost outline
When does fat necrosis occur?
-During injury to adipocytes or fatty tissue
What organ typically undergoes fat necrosis and when?
-Pancreas during acute pancreatitis
What does fat necrosis release?
-Free FA
What is the association between calcium and fat necrosis?
-Calcium deposits in abdomen
What is apoptosis?
-Programmed cell death with shrinkage
Why is apoptosis described as an active process?
-Requires ATP
What are caspases?
-Enzymes which are activted during apoptosis and degrade the cell’s DNA and proteins in an organised and scheduled manner
How is apoptosis activated intrinsically to the cell?
- Leakage of cytochrome C from mitochondria
- Interacts wih APAF1 and Caspase-9 to form apoptosome
- Apoptosome activates downstream caspases
What is the usual cause of intrinsic activation of apoptosis?
- DNA damage
- Hormone withdrawal
Describe extrinisic activation of apoptosis
-Binding of death ligand to death ligand receptor activates caspases
When are death ligand receptors expressed on a cell?
-In response to damage
Name 2 death ligands
- TRAIL
- FAF
What is the differences between blebbing and budding?
- Blebbing is disorganised disruption of the cell membrane and the blebs do not contain cellular material
- Budding is organised rearrangement of cytoskeleton and the apoptotic bodies may contain cellular material
What happens to the nuclear fragments and apoptotic bodies produced by apoptosis?
-They are phagocytosed by phagocytes or removed by neighbouring cells
Is apoptosis pathological or physiological?
- Often physiological eg eliminating unwated cells
- Can be pathologic after some forms of cell injury
Do the cells disintegrate in apoptosis like in necrosis?
-No, there is chromatin condensation and nuclear fragmentation
What is chracteristic of the membrane throughout apoptosis?
-Stays intact
Does apoptosis occur in groups of cells or singly?
-Single cells
What is gangrene?
-Grossly visible necrosis
What is the treatment for gangrene?
-The dead tissue needs to be removed
What is dry gangrene?
-Coagulative necrosis modified by the air to become dry gangrene
Give an example of dry gangrene
-Umbilical cord after birth
What is wet gangrene?
-Liquefactive necrosis modified by bacteria to form wet gangrene
Why is wet gangrene more dangerous than dry gangrene?
-The bacteria can leak into the blood and cause septicaemia
What is gas gangrene?
-Necrotic tissue becomes infected with anaerobic bacteria which produce gas which appears as bubbles/blisters under the skin
When is gas gangrene frequently seen?
-In motorbike injuries as soil/gravel/dirt enters the wound upon impact
What is an infarct?
-Necrosis due to ischaemia
What are the frequent causes of infarcts?
- Thrombosis
- Embolism
- Compressional twisting
Give examples of compressional twisting
- Twisting of colon
- Haemorrhoid
- Testicular torsion
What determines the type of necrosis which occurs during an infarct?
- Whether there is an alternative blood supply
- The speed of ischaemia
- The tissues involved
What detemines whether the infarct is white or red?
-The level of haemorrhaging
Why is the occlusion of an end artery a white infarct?
-No peripheral blood vessels which leaves the area entirely without blood and thus there is no haemorrhaging
In what type of organs does white infarct occur and why?
-Solid organs as the amount of haemorrhage that occurs from adjacent capillaries is limited
Why does red infarct occur in tissues with dual blood supply?
-Occlusion of one vessel, the other vessel is not sufficient to maintain cells and tissue dies with haemorrhaging occuring
Why does red infarct occur in loose tissue?
-There is poor stromal support for adjacent capillaries and they burst
How does venous insufficiency cause red infarct?
-Increased venous pressure decreases arterial blood flow which leads to ischaemia and infarct however blood flow is still present, just not sufficient
What is hyperaemia and what type of infarct occurs?
- Increased blood flow to a specific tissue
- Red
What type of infarct occurs if there is reperfusion?
-Red
Why is high levels of potassium in the blood extremely dangerous?
-Stops the heart beating
Under what pathlogical conditions is it possible to get high levels of potassium in the blood?
- Large myocardial infarction (high levels of local potassium release)
- Severe burns (high levels of cellular necrosis)
- Tourniquet shock (removed quickly after several hours)
- Tumour lysis syndrome
What is tumour lysis syndrome?
-Paradoxical effect form successful chemotherapy ->High number of cancerous cells killed and broken down at once releasing lots of potassium
How are enzymes in the blood useful after cell injury?
- Concentrations of specific enzymes in the blood indicate which organs have been effected severly and for how long
- Small enzymes released first as the gaps in membranes are small, as damage progresses the gaps become bigger and larger enzymes can leak out
Why are high levels of myoglobin in the blood dangerous after cell injury?
- Released from dead myocardium and striated muscle
- Rhabdomyolysis -> myoglobin plugs renal tubules and leads to renal failure
What are common causes of rhabdomyolysis?
- Trauma
- Burns
- Alcohol/drug abuse
What is the result of abnormal accumulation of water and electolytes?
-Swelling and oedema
What is the result of abnormal lipid accumulation?
- Hepatic steatosis (fatty liver)
- Cholesterol in atherosclerotic plaques
- Xanthomas
What is a result of abnormal protein accumulation due to alcoholic liver disease?
-Mallory’s hyaline (an accumulation of keratin in the liver)
How does a-1 antitrypsin deficiency lead to liver cirrhosis?
-Abnormal folding of proteins leads to accumulation of protein in the liver which leads to cirrhosis
Name 2 exogenous abnormal accumulations of pigment
- Coal dust picked up by alveolar marcrophages (pneumoconiosis)
- Tattoos (pigment can be taken to lymph nodes)
What is lipofuscin?
- An endogenous pigment which appears with age in the myocardium, neurones and hepatocytes
- Has no pathological consequences
What is haemosiderin?
-Iron storage molecule
What is haemosiderosis?
-The accumulation of haemosiderin in various tissues
What is hereditary haemochromatosis?
- Bronze diabetes
- Increased intestinal absorbtion of iron leads to deposition in skin, liver pancreas and heart
What is pathological calcification?
-Abnormal deposition of calcium salts in tissues
What is dystrophic calcification?
-Local calcium deposition which occurs in areas of dying tissue (eg damaged heart valves)
What causes dystrophic calcification?
-There is no abnormality in calcium metabolism, it is caused by local changed which promote hydroxyapatite depositions in tissues
What are the outcomes of dystrophic calcification?
-Can cause organ dysfunction but can also be harmless
What valve never calcifies?
-Pulmonary
What is metastatic calcification?
-Hydroxyapatite deposition whih is systemic when there is hypercalcaemia
What are the main causes of metastatic calcification?
- Oversecretion of PTH (parathyroid adenoma, renal failure with retention of phosphate causing high levels of PTH)
- Ectopic secretion of PTHrp from malignant tumours (esp. lung)
- Destruction of bone tissue (primary tumours, padgets disease)
What is replication senescence?
-Cells loose their ability to replicate as they age
What happens to telomeres as cells age?
-They reduce in size per each round of replication
What are telomerases and which cells have them?
- Enzymes which can re-lengthen telomeres so replication can be indefinite
- Stem cells, germ cells and some cancer cells
What are the stages of liver disease from chronic excessive alcohol intake?
- Steatosis
- Acute alcoholic hepatitis
- Cirrhosis
What are the features of alcoholic liver disease?
- Focal hepatocyte necrosis
- Mallory body formation
- Accumulation of neutrophils
- fever
- Liver tenderness
- Nausea
- Vomiting
- Jaundice
Describe a cirrhotic liver
-Hard, shrunken nobbly liver with micronodules of regenerating hepatocytes separated by scar tissue
What stage of liver damage becomes irreversible?
-Cirrhosis
