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Cell Injury Flashcards

0
Q

What are the 3 mechanisms by which hydroxyl radicals can be formed?

A

Direct lysis of water by radiation
Fenton reaction - Fe2+ plus hydrogen peroxide gives Fe3+, hydroxide ions and hydroxyl radicals
Haber-Weiss reaction - superoxide radicals plus a proton and hydrogen peroxide give molecular oxygen, water and hydroxyl radicals.

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1
Q

Which 3 free radicals are of particular significance?

A

Hydroxyl (most dangerous)
O2- (superoxide)
H2O2 (hydrogen peroxide)

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2
Q

What is meant by Oxidative Stress?

A

When there is an imbalance between free radical production and radical scavenging by the anti-oxidant system, allowing the radicals to build up in the cell/tissue
This causes cell injury

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3
Q

What are the 2 key enzymes involved in the anti-oxidant system?

A

Superoxide dismutase which forms hydrogen peroxide from superoxide (hydrogen peroxide is less toxic to cells)
Catalases and peroxidases complete the free radical removal, forming oxygen and water from hydrogen peroxide.

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4
Q

Apart from the 2 key enzymes, what are 2 other important components of the anti-oxidant system?

A

Free radical scavengers that neutralise the radicals e.g. Vitamin A, C and E and Glutathione
Storage proteins in the ECM such as transferrin and ceruloplasmin sequester transition metals such as iron and copper (which usually help catalyse formation of radicals)

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5
Q

What is the role of heat shock proteins (molecular chaperones)?

A

Upkeep of cellular proteins
Important when folding of proteins goes astray or when cell injury denatures proteins
Unfold and ensure correct refolding of proteins
If refolding cannot occur then they signal cell to destroy the misfolded protein

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6
Q

What are the 3 main alterations to cells when injured that we can see using only a light microscope?

A

Cytoplasmic changes - reduced pink staining as we get reversible accumulation of water. This can be followed by increased pink stain due to detachment of ribosomes and accumulation of abnormal denatured proteins (irreversible)
Nuclear changes - chromatin clumps (reversible), and this may then be followed by pyknosis (shrinkage), karryohexis (fragmentation) and karryolysis (dissolution) of nucleus (irreversible changes)”
Abnormal intracellular accumulations

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7
Q

What are the 4 reversible changes that we can identify using an electron microscope?

A

Swelling of cell and organelles due to sodium pump failure
Cytoplasmic blebs due to the cell swelling
Clumped chromatin due to reduced pH
Ribosome separation due to failure of energy-dependent process of maintaining ribosomes in the correct location

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8
Q

What are the 7 irreversible changes seen under an electron microscope?

A

Further cell swelling
Nuclear changes - pyknosis. Karryohexis, and karryolysis
Swelling and rupture of lysosomes
Membrane defects
Myelin figures (damaged membranes)
Lysis of the Endoplasmic reticulum due to membrane defects
Amorphous densities in swollen mitochondria

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9
Q

What is the difference between oncosis and necrosis?

A

Oncosis is a term for the spectrum of changes that occur in injured cells before they are considered as being dead
Necrosis refers to the morphological changes that come after the death of a cell in living tissue (largely due to the progressive degradation action of enzymes like crows around a carcass)

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10
Q

Define Apoptosis

A

Cell death induced by a regulated intracellular program where a cell activates enzymes that degrade it’s own nuclear DNA and proteins

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11
Q

What actually happens in a cell during necrosis?

A

Damage to membranes surrounding the cell and also the organelles allowing lysosomal enzymes to be released into the cell cytoplasm, where they start to internally digest the cell.
Cell contents are able to leak out of the cell and inflammation is often seen

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12
Q

What happens to a tissue following necrosis?

A

The necrotic tissue is removed by enzymatic degradation and phagocytosis by white blood cells.
Any remaining necrotic tissue may calcify in the process of DYSTROPHIC CALCIFICATION

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13
Q

What determines whether we see coagulation or liquefaction necrosis in a tissue?

A

Balance between protein desaturation and release of active enzymes
When desaturation is the dominant process proteins “clump” leading to solidity of the dead cells. This happens in most solid organs when cause of death is ischaemia.
When release of active enzymes is dominant (especially proteases) the dead cells start to liquefy. This is associated with a large number of neutrophils

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14
Q

What can be seen in coagulative necrosis?

A

Histological “ghost outline” of cells as cellular architecture is somewhat preserved even upon cell death.
After a few days appearances are modified by the fact that the dead tissue incites an acute inflammatory reaction with consequent phagocytic infiltration

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15
Q

What is meant by caseous necrosis and where is it commonly seen?

A

Can look like cheese macroscopically
Amorphous debris (no ghost outlines like in coagulative)
Particularly associated with infections such as TB
Often associated with granulomatous inflammation

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16
Q

When can fat necrosis occur?

A

Destruction of adipose tissue
Seen in acute pancreatitis - inflammatory release of lipases from injured acinar cells
These lipases act on and destroy fatty tissue in the pancreas and also elsewhere in the abdominal cavity
Can also occur after direct trauma to fatty tissue e.g. In the breast where healing leaves a nodule of scar tissue that can mimic a tumour

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17
Q

What is a consequence of fat necrosis?

A

Release of free fatty acids which can react with calcium which is also around in cell injury to form chalky deposits called “calcium soaps” in the fatty tissue
We can see this chalk on x-rays and also with the naked eye during surgery and autopsy

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18
Q

What is gangrene?

What are the 2 types?

A

Not a type of necrosis but rather a term used to describe necrosis that is visible to the naked eye
DRY - coagulative necrosis
WET - liquefactive necrosis, typically seen in infections and can result in septicaemia.

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19
Q

What is a Infarction?

A

A CAUSE of necrosis, namely ischaemia (reduced blood supply)

Area of tissue death caused by obstruction to blood supply is an infarct (can result in gangrene)

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20
Q

What is meant by a white infarct?

A

Occur in solid organs (good stromal support)
Occlusion of end artery
Solid nature of tissue limits amount of haemorrhage that can occur into infarct from adjacent capillaries
Tissue supplied by end artery appears pale due to lack of blood
Kidneys, heart and spleen
Wedge-shaped (occluded artery at apex of wedge)
Coagulative necrosis

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21
Q

What is meant by a red infarct?

A

Extensive haemorrhage into dead tissue

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22
Q

What are the 5 situations in which a red infarct can occur?

A

Organs with dual blood supply e.g. Lung (second supply cannot rescue the dead tissue but blood can still enter the tissue)
Numerous anastomoses (where capillary beds if 2 separate arterial supplies merge) e.g. In intestines
In loose tissue e.g. Lung where poor stromal support for capillaries means more haemorrhage than usual out of them
Where there has been previous congestion - already more than the usual amount of blood in the necrotic tissue already
Raised venous pressure - pressure transmitted to capillary bed and as tissue pressure increases eventually there is reduced arterial filling causing ischaemia and subsequent necrosis, with a red infarct because tissue engorged with blood

23
Q

What can the consequences of an infarction depend on?

A

Whether tissue has an alternative blood supply
Speed of ischaemia (gradual allows time for additional perfusion pathways to develop)
How vulnerable a tissue is to hypoxia
Oxygen content of blood

24
What are 2 physiological examples of apoptosis?
When cells no longer needed are removed to maintain a "steady state" during hormone-controlled involution and in cytotoxic T cell killing if virus-infected or neoplastic cells Also seen in embryogenesis, in web spaces
25
What actually happens during apoptosis?
Cell activates enzymes that degrade it's own nuclear DNA and proteins Membrane integrity maintained throughout the process Energy source needed
26
What can we see under the light microscopic for apoptosis?
Cells are shrunken and intensively eosinophilic. | Cell shrinkage, chromatin condensation, pyknosis and nuclear fragmentation
27
What do apoptotic cells look like under the electron microscope?
Cytoplasmic blebs which progress to fragmentation into membrane-bound apoptotic bodies containing cytoplasm, organelles and often also nuclear fragments These apoptotic bodies are eventually removed by macrophages. No leakage of cell contents so no inflammation
28
What are the 3 phases of apoptosis?
Initiation Execution Degradation/phagocytosis
29
What are caspases?
Proteases that mediate the cellular effects of apoptosis | Cleave proteins, breaking up the cell cytoskeleton and initiating DNA degradation
30
What is INTRINSIC APOPTOSIS?
Central player is mitochondria All apoptotic machinery is within cell (hence intrinsic) P53 protein is an important player Various triggers such as DNA damage and removal of growth factors lead to increased mitochondrial permeability thus releasing cytochrome C Cytochrome C interacts with APAF1 and caspase 9 to form an APOPTOSOME that activates various downstream caspases
31
What is meant by EXTRINSIC apoptosis?
Receptor-mediated apoptosis caused by external Ligands such as TRAIL and Fas that bind to "death receptors" Leads to caspase activation independently of mitochondria
32
What happens in the degradation phase of apoptosis?
Cell breaks into membrane bound APOPTOTIC BODIES | These express molecules on surface that induce phagocytosis of apoptotic bodies by neighbouring cells or phagocytes
33
What are the 6 main apoptotic molecules and briefly state the role of each
P53 - "guardian of the genome", this mediates apoptosis in response to DNA damage Cytochrome C, APAF1, caspase 9 - together these are the APOPTOSOME Bcl-2 - prevents cytochrome C release from mitochondria, inhibiting apoptosis Death Ligands - TRAIL Death receptors - TRAIL-R Caspases - effector molecules of apoptosis e.g, caspase 3
34
What may abnormal cellular accumulations be like?
Reversible and harmless or toxic Can consist of normal cellular constituents e.g. Water, lipids, proteins, carbohydrates etc. May consist of abnormal substances, whether exogenous or endogenous such as products of abnormal metabolism Can also be pigments
35
What is steatosis?
Accumulation of triglycerides Often seen in liver (major organ of fat metabolism) Caused by alcohol abuse, DM, obesity and toxins such as carbon tetrachloride
36
What are cholesterol accumulations like?
Within smooth muscle and macrophages within atherosclerotic plaques Cells have foamy cytoplasm - FOAM CELLS Xanthomas in skin and tendons
37
What do protein accumulations look like? | What is Mallory's Hyaline?
Eosinophilic droplets in cytoplasm | Damaged protein seen in hepatocytes in alcoholic liver disease, due to accumulation of altered keratin filaments
38
What happens in alpha1 anti trypsin deficiency?
Liver produces incorrectly folded version of alpha 1 anti trypsin Cannot be packaged by ER and so accumulates here, not secreted by liver as it should be Deficiency of enzyme in body means that proteases in the lung are not controlled and so break down lung tissue e.g. Elastase in emphysema
39
What is a good example of exogenous pigment accumulation?
Coal workers pneumoconiosis Urban air pollutants such as Coal can be inhaled and phagocytosed by macrophages in lungs The lung tissue will therefore appear blackened If exposure is particularly high the lungs can become fibrotic and emphysematous
40
What are 3 examples of endogenous pigments?
Lipofusin - brown pigment in aging cells, sign of previous free radical injury and lipid peroxidation Haemosiderin - derived from Hb, forming where there is a systemic or local excess of iron e.g. In the skin as a bruise. Haemosiderosis is when systemic iron is high and haemosiderin deposits in many organs - seen in haemolytic anaemias etc, and when the haemosiderosis is severe we can get organ damage Bilirubin is a bile pigment which causes jaundice when the liver is not functioning properly or in haemolytic anaemias.
41
What is meant by DYSTROPHIC CALCIFICATION?
Abnormal deposition of calcium salts in areas of dying tissue, in atherosclerotic plaques, in aging heart valves and in TB lymph nodes. No abnormality in calcium metabolism or serum calcium concentration Can cause organ dysfunction
42
What is METASTATIC CALCIFICATION?
When calcium deposited in tissues where there is hypercalcemia secondary to disturbed calcium metabolism. Usually asymptomatic
43
What are the 4 main causes of hypercalcemia?
Increased PTH resulting in bone resorption (May be due to tumours of PTH gland or ectopic secretion of PTH-related protein by malignant tumours Destruction of bone secondary to primary bone tumours, bone metastasis, Paget's disease or immobilisation Vitamin D related disorders Renal failure
44
What happens to cells as they age?
Accumulate damage to cell constituents and DNA May accumulate lipofuscin pigment and abnormally folded proteins Decreased ability to replicate (replicative senescence)
45
What is the process of alcohol metabolism? | What is the problem with chronic excessive alcohol intake?
Ethanol converted to acetaldehyde by alcohol dehydrogenase, the CYP450 isoenzyne CYP2E1 and catalase Acetaldehyde is converted to acetic acid by aldehyde dehydrogenase Results in physical and psychological dependence on alcohol
46
What happens in women and 50% of oriental people?
Women have lower concentrations of alcohol dehydrogenase so have higher blood alcohol concentration than men who have drunk the same amount Orientals have reduced activity of aldehyde dehydrogenase so acetaldehyde builds when they drink, resulting in symptoms such as facial flushing and extreme hangovers.
47
What are the 3 effects of excessive alcohol on the liver?
Fatty change - toxicity results in steatosis which can cause hepatomegaly. This is acute, reversible and asymptomatic Acute alcoholic hepatitis - focal hepatocytes necrosis, formation of Mallory bodies and a neutrophilic infiltrate. Can give symptoms of fever, liver tenderness and jaundice, usually reversible Cirrhosis - hard shrunken liver in 10-15% alcoholics! see micro nodules of regenerating hepatocytes surrounded by bands of collagen. Irreversible and serious, can even be fatal
48
How is paracetamol detoxified in the liver?
By sulphonidation and glucuronidation | Small amounts metabolised by CYP2E1 (oxidised) to the toxic metabolite NAPQI, which can be detoxified via glutathione.
49
What happens in paracetamol overdose?
Glutathione depleted and NAPQI accumulates Binds with sulphydryl groups on liver cells causing hepatocytes necrosis and eventually liver failure If the overdose is massive necrosis can occur in 3-5 days
50
In which groups of people is a paracetamol overdose very worrying and why?
Those who had alcohol too People who are alcohol-dependent Malnourished people People on enzyme inducing drugs such as carbamazepine People who are HIV positive or who have AIDs These people have lower reserves of glutathione
51
How can a paracetamol overdose be treated?
Give N-acetylcysteine to increase availability of hepatic glutathione
52
What is the prothrombin time (INR)?
Measured 24 hours after overdose this is a guide to severity of liver damage
53
What is aspirin?
Drug which acetylates platelet cyclo-oxygenase and blocks ability of platelets to make thromboxane A2 (necessary for platelet aggregation)
54
How does aspirin affect the body's pH?
Stimulates respiratory centre which causes respiratory alkalosis. Compensatory mechanisms then result in metabolic acidosis
55
What are some consequences of aspirin overdose?
Interfere with carbohydrate, fat and protein metabolism and OP Results in increased lactate, pyruvate and ketone bodies, all of which contribute to acidosis Can cause acute erosive gastritis causing GI bleeding

Mechanisms Of Disease (3 decks)

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