MOD Flashcards
What is hypoxaemic hypoxia? Give an example of something that might cause this.
Arterial saturation of oxygen is low. E.g. Altitude
What type of hypoxia would be caused by carbon monoxide poisoning?
Anaemic hypoxia - reduced ability of red blood cells to carry oxygen
What is meant by histocytic hypoxia? Give an example of an agent that might cause this.
Reduced ability of cells to utilise oxygen due to disabled oxidative metabolism enzymes.
Can be caused by cyanide poisoning
Why is ischaemic hypoxia the most severe type?
Due to the loss of nutrients as well as oxygen
During cellular hypoxic injury, what is the first thing to happen?
Switch to glycolysis (anaerobic metabolism) for ATP production
During hypoxic cell injury, what is the major consequence of switching to glycolysis for metabolism?
Build up of lactate causes a drop in cellular pH. Alters enzyme activity and causes chromatin clumping
Why does cell swelling occur during cell injury?
Sodium pump activity is lost due to decreased ATP levels. Sodium accumulates in the cell raising the osmotic pressure so that water follows. Calcium also enters the cell through damaged membrane and from intracellular stores.
Explain why you see intracellular accumulations of denatured proteins in cell injury.
ATP required for ribosome attachment to the ER. Therefore, low levels of ATP result in disrupted protein synthesis and denatured proteins accumulate.
What 4 enzymes does the increase in Cytosolic calcium seen in cell injury activate?
Phospholipases, proteases, ATPases, endonucleases
How long can neurones of the brain tolerate hypoxia?
2 to 5 mins
How long can dermal fibroblasts and skeletal muscle tolerate hypoxia for?
2-6 hours
Explain how Oncosis in a tissue can be detected?
Enzymes from that tissue in the blood due to the damaged membrane of the cells during prior to Oncosis (e.g. Transaminase in liver, troponin C in heart)
What are the three theories for ischaemic reperfusion injury?
- Increased production of free radicals
- Increased number of neutrophils causing inflammation
- Delivery of complement components
What is meant by oxidative stress?
An imbalance between free radical production and free radical scavenging
Name the 4 types of hypoxia.
Hypoxaemic, anaemic, histocytic, ischaemic
What is a free radical?
A reactive oxygen species with a single unpaired electron in its out orbit.
Give 3 ways by which reactive oxygen specie OH can be produced.
- Radiation directly lyses water
- Fenton equation where H2O2 reacts with Fe3+ ions
- Haber-Weiss reaction where O2- reacts with H2O2 and H+ to generate O2, H20 and OH.
Explain why reactive oxygen species may be generated during bleeding.
Due to the Fenton reaction where H202 reacts with Fe3+ ions which are now readily available in the blood.
How do storage proteins such as transferrin and Ceruloplasmin act as anti-oxidants?
They sequester transition metals, such as iron and copper, in the extracellular matrix to prevent them entering cells and producing free radicals.
What type of protein is released in cell injury in all cell types?
Heat shock proteins
What is the role of heat shock proteins?
Give an example of one.
They maintain protein viability of the injured cell by attempting to refold denatured or Mis-folded proteins or targeting them for destruction.
E.g. Ubiquitin
What is the best way to diagnose cell death?
Functionally - using dye exclusion technique where dead cells will soak up dye-stained medium.
What are the 3 changes to the nucleus of a cell undergoing irreversible cell injury and oncosis?
Pyknosis (shrinkage), karryonexis (fragmentation), karryolysis (dissolution)
What changes might you see under the light microscope in cells undergoing cell injury that is still reversible?
Reduced pink staining (due to water), clumped chromatin, intracellular accumulations (protein)
Why might you see increased pink staining in the cytoplasm of irreversibly injured cells?
As ribosomes detach from the ER and are lost in the cytoplasm
As well as cell swelling and nuclear changes, what else might you expect to see in irreversible cell injury under the electron microscope?
Lysosome swelling & rupture, membrane defects, myelin figures, ER lysis, swollen mitochondria with amorphous densities and cell blebbing
Define ‘Oncosis’.
Cell death with swelling.
Define ‘apoptosis’.
Cell death with shrinkage - induced by a regulated intracellular program
Define ‘necrosis’.
The morphological changes that occur after a cell has been dead some time.
Over what period does necrosis of dead tissue tend to occur?
4-12 hours after cell death
What are the 2 major types of necrosis?
Coagulative & liquifactive
What is meant by coagulative necrosis?
The proteins of the cell undergoing necrosis denature and coagulate together leading to solidity of the dead cells and tissue.
How would coagulative necrosis appear under the microscope?
Pale in colour, ghost outline of cells still present as cellular architecture is preserved
What is meant by liquifactive necrosis?
The proteins of the cell undergoing necrosis undergo dissolution by the cell’s enzymes (proteases) - leads to the tissue become liquified.
When is liquifactive necrosis commonly seen?
In tissues lacking a robust collagenous matrix (e.g. The brain), or in necrosis associated with large numbers of neutrophils (e.g. In bacterial infection)
What are the 2 rarer types of necrosis?
Caseous and fat necrosis
What is caseous necrosis associated with?
Granulomatous inflammation - e.g. TB.
What does caseous necrosis look like?
Lots of white, amorphous debris (cheesy appearance)
What disease is fat necrosis associated with and why?
Acute pancreatitis because of release of lipases from injured acinar cells which act on surrounding fatty tissue
Other than acute pancreatitis, what is another cause of fat necrosis?
Direct trauma to adipose tissue, e.g. The breast
What is gangrene?
A clinical term used to describe necrosis that is visible to the naked eye
Differentiate between the 2 types of gangrene.
Wet = infection present in area undergoing necrosis so underlying process is liquifactive.
Dry = exposure of area to air results in drying (e.g. Umbilical cord) so underlying process is coagulative.
What is gas gangrene?
Wet gangrene infected with anaerobic bacteria producing visible and palpable bubbles in the tissue.
What is an infarct?
An area of tissue undergoing Oncosis and necrosis as a result of loss of blood supply (Ischaemia).
What is a ‘white infarct’?
Infarction after occlusion of an end artery with little anastomoses. The tissue appears white because there is minimal haemorrhaging from adjacent vessels.
Name 3 tissues in which a white infarct usually appears after ischaemia.
Heart, kidney, spleen
What is a ‘red infarct’?
Extensive haemorrhaging occurs into the area of infarction (necrosis following ischaemia) so that the tissue appears red.
Give 2 tissues which usually present with a red infarct following ischaemia and explain why.
Lungs and intestines because they have a dual blood supply with many anastomoses.
Why would a red infarct, rather than a white, occur in congestive heart failure?
Because there has been previous congestion with more than usual amounts of blood around.
Give 3 physiological reasons why apoptosis might occur.
Cell no longer needed, hormone-controlled Involution, Tc cell killing infected (virus or neoplastic) cell, embryogenesis,
Give 2 pathological reasons why a cell might undergo apoptosis.
Toxic injury or tumour cell
How long does apoptosis take?
Very quick - cell gone within a few hours
What might you see under the microscope when looking at an apoptotic cell?
Shrunken cell, eosinophilic colour, chromatin condensation, pyknosis, karryohexis, cytoplasmic budding, membrane-bound apoptotic bodies.
What is contained within apoptotic bodies?
Cytoplasm, nuclear fragments and organelles
Explain why inflammation generally occurs around sites of oncosis but not apoptosis.
In apoptosis, there is no leaking of cell contents and enzymes
What are the differences between intrinsic and extrinsic initiation of apoptosis?
Intrinsic = triggered by internal DNA damage, a hormone or growth factor withdrawal. Mitochondria are the central player.
Extrinsic = triggered by external ligands (e.g. Fans or TRAIL) binding to death receptors and caspases are activated independently of the mitochondria.
Once initiated by DNA damage or hormones (growth factor), explain the process of apoptosis execution in the intrinsic pathway.
The mitochondrial permeability is increased and cytochrome C is released. This interacts with APAF1 and caspase 9 to form an apoptosome which activates downstream caspases.
How are apoptotic cells phagocytosed?
They break down into membrane bound fragments called apoptotic bodies which express surface molecules that induce phagocytosis by phagocytes.
How do caspases work?
They mediate apoptosis by cleaving proteins - break up the cytoskeleton and initiate DNA degredation.
What are the 2 substances released from most tissues undergoing massive necrosis?
Potassium and enzymes
Explain why release of potassium from large numbers of necrosing cells is dangerous.
When might this happen?
Hyperkalaemia is dangerous to the heart and can cause it to stop beating.
Happens in MI, burns, torniquet shock or tumour lysis syndrome
What is released from dead myocardium or skeletal muscle?
Why is this dangerous?
Myoglobin.
Can cause rhabdomyolysis which may result in renal failure.
Name 4 substances that are known to accumulate in cells in chronic cell injury.
Water & electrolytes.
Proteins.
Lipids.
Pigments.
In what 2 ways can water accumulate in a cell?
As vacuoles or cause cell swelling
What is hydropic swelling?
Cell swelling due to water-logging of the entire cell
What is the accumulation of triglyceride lipids called?
Steatosis
Give 4 causes of liver steatosis and 3 signs.
Causes - alcohol abuse, diabetes, obesity, toxins.
Signs - yellow-coloured liver, hepatomegaly, greasy liver on post-mortem
In addition to triglycerides, what other type of lipid tends to accumulate?
Cholesterol
Name 4 places cholesterol accumulates.
Macrophages and smooth muscle cells = foam cells.
Skin and tendons = xanthomas
What is mallory’s hyaline and when/where is it seen?
The accumulation of damaged keratin (intermediate) filaments in hepatocytes of people with alcoholic liver disease.
What is the major sign of alpha1-antitrypsin deficiency?
What can result from this disorder?
Accumulation of proteins in the ER due to abnormally folded protein that is no secreted.
Results in emphysema as proteases act unchecked.
Name 2 exogenous pigments that can accumulate in macrophages and lymph nodes.
Coal dust / soot and tattoo ink.
Name 3 endogenous pigments that can accumulate in cells.
Lipofuscin, bilirubin & haemosiderin
What is lipofuscin?
An age-pigment that accumulates in cytoplasm of cells - made up of a polymer of oxidised, indigestible, brown, intracellular lipids.
What is haemosiderin and why is it of clinical relevance?
A yellow-brown iron storage molecule that can accumulate locally (in a bruise) or systemically (haemosiderosis) in excess of iron.
Give 3 causes of haemosiderosis (systemic excess of iron).
Haemolytic anaemia, regular blood transfusions or haemochromatosis genetic disorder.
What is ‘bronzed diabetes’, and what is it indicative of?
Pancreatic failure where the pancreas is abnormally yellow/brown. Indicative of haemochromatosis - a genetic disorder of increase iron uptake that results in iron being deposited in organs, including the pancreas.
What is bilirubin?
The breakdown product to haemoglobin = a stack of porphyrin rings that have lost their iron and are fragmented.
Where is bilirubin usually eliminated?
In the bile
What is the clinical term for the symptom of raised bilirubin levels?
What 3 things can cause this?
Jaundice.
Bile duct obstruction (gallstones), liver disease, haemolytic anaemia.
What is dystrophic calcification?
Deposition of calcium salts in tissues locally with no abnormality in calcium metabolism or levels.
Give 4 examples of where dystrophic calcification is common.
Dying tissue, atherosclerotic plaques, ageing or damaged heart valves, tuberculous lymph nodes
In which heart valve does dystrophic calcification not occur?
Pulmonary - more acidic blood
What is it called when there is systemic pathological calcification?
Metastatic calcification
What is the cause of metastatic calcification?
Hypercalcaemia. Due to increased PTH secretion or destruction of bone tissue.
What is Paget’s disease of the bone and what can it result in?
A disease where there is increased turnover of bone. May result in metastatic calcification.
What enzyme do germ, stem and tumour cells contain that gives them indefinite replication?
Telomerase - maintains original length of telomeres
What are the 4 symptoms of an ageing cell?
- Accumulation of damage to cell consitituents and DNA
- Lipofuscin accumulation
- Accumulation of abnormally folded proteins
- Replication senescence.
What are the 3 changes that occur to the liver in excessive alcohol intake?
- Steatosis
- Hepatitis (mallory’s bodies and neutrophils & necrosis)
- Cirrhosis
What is the structure of a cirrhotic liver?
Micro-nodules of regenerating hepatocytes surrounded by bands of collagen.
What is the definition of inflammation?
A response to injury of vascularised living tissue intended to deliver blood cells and fluid to the site.
What is meant by acute inflammation being ‘stereotyped’?
It is the same on every occasion
WHat are the 3 functions of inflammation?
Protect against infection.
Clear damaged tissue.
Initiate tissue repair.
Give 6 general causes of acute inflammation.
- Foreign bodies.
- Immune reactions
- Infection
- Tissue necrosis
- Trauma
- Physical and chemical agents
What type of infectious agent is especially causing of acute inflammation?
Pyogenic (pus-forming)
What are the 5 classical symptoms of acute inflammation?
Rubor (redness) Tumour (swelling) Dolor (pain) Calor (heat) Loss of function
What are the 3 characteristic tissue changes of acute inflammation?
- Vascular flow
- Fluid Exudation
- Neutrophils infiltration
What are the 5 vascular flow changes that occur in acute inflammation?
- Transient vasoconstriction
- Vasodilation
- Increased permeability
- Increased vessel resistance
- Stasis of blood flow in local circulation
Explain why there is stasis of blood flow in acute inflammation?
Proteins, while blood cells and plasma fluid leave the blood and enter the tissues therefore increasing the haematocrit and viscosity of the blood.
What chemical mediator is especially associated with the vascular changes of acute inflammation?
Which cells secrete it?
Histamine.
Secreted by mast cells, basophils and platelets.
What triggers histamine release?
Physical damage, immunological reactions, complement, IL-1
Why does fluid leave the vessels in acute inflammation?
A increased hydrostatic pressure within the vessels forces fluid out and an increase in colloid osmotic pressure of the interstitium as protein leaves through the permeable vessel walls.
What are the 3 main functions of fluid Exudation in acute inflammation?
- Delivery of plasma proteins to injury site, e.g. Fibrin
- Excess fluid drained by lymphatics taking micro-organisms to lymph nodes
- Dilution of toxins causing the damage
Define oedema.
Excess fluid in the interstitium.
What are the major differences between transudate and exudate?
Transudate occur in normal vessels without a change in permeability or colloid osmotic pressures. It is due to changes in hydrostatic pressure (e.g. Cardiac failure). Oedema has a low protein content.
Exudate occurs in inflammation where there is increased vascular permeability, and decreased colloid osmotic pressure within the blood as well as increased hydrostatic pressure. Hence the oedema has a high protein content.
Where is serotonin released from and what are its actions?
Mast cells and platelets. A vasoactive amine - vasodilation, increased permeability and fibroblast stimulation
Where are prostaglandins released from and what is there role in acute inflammation?
Phospholipids of most cells.
Vasodilation, pain sensitivity and fever.
What is the role of bradykinin in acute inflammation?
Increases pain sensitivity and vascular permeability.
Name 2 cytokines of acute inflammation that rearrange the cytoskeleton of endothelial cells.
IL-1 and TNF
What is the main role of VEGF in acute inflammation?
Increases transcytosis - the number of channels across endothelial cytoplasm allowing fluid to pass.
What 4 important proteins does exudate contain that are crucial for acute inflammation?
Fibrin, complement, antibodies and opsonins
What are the 3 main roles of complement components?
Inflammatory mediators, opsonisation and production of membrane attack complex (bacteria perforating structure)
What is the primary cell type involved with acute inflammation?
Neutrophils
What is the lifespan of neutrophils?
12-20hours
How fast do neutrophils move?
30um/min
Define chemotaxis.
The movement of cells along a concentration gradient of chemoattractants.
Name 7 chemoattractants.
Bacterial products (Endotoxin), injured tissue, leukotriene B4, thrombin, fibrin degredation products, complement (C5a and C3a), chemokines
Describe the activation of neutrophils.
On binding of chemotaxis to neutrophil, calcium and sodium enter the cell causing cell swelling and cytoskeletal reorganisation. This forms pseudopodia in the direction of the chemotaxin.
What is the process of margination?
Neutrophils adhering to the endothelial surface of blood vessels.
What molecules help rolling of the neutrophils?
Selectins
What molecules are responsible for adhesion of neutrophils?
Integrins
How do leucocytes such as neutrophils get through the blood vessel wall?
Diapedesis - collagenase production to digest basement membrane.
Name 2 opsonins.
IgG and C3b
By what 2 mechanisms do neutrophils kill their phagocytosed organisms?
- Oxygen dependent = respiratory burst
2. Oxygen independent = enzymes (proteases, nice lashes, phospholipases and lysozyme)
List the 6 steps do neutrophil infiltration in acute inflammation.
Chemotaxis, activation, margination, diapedesis, phagocytosis, killing
What is the half life of a chemical mediator?
Seconds to minutes
Describe the formation of prostaglandins and Leukotrienes.
Conversion of phospholipids to aracadonic acid by phospholipid A2.
Arachadonic acid converted to Leukotrienes or prostaglandins & thromboxanes by lipoxygenase or cycloxygenase respectively.
What 2 drugs inhibit cyclo-oxygenase?
What effect will this have?
NSAIDs & aspirin. = reduced prostaglandin and thromboxane production.
What is the chemical mediator bradykinin derived from and how?
Kininogen in the blood by kallikrein enzyme which cleaves it
Name the 4 vasoactive chemical mediators of acute inflammation.
Prostaglandins, histamine, serotonin, bradykinin
Name the 2 chemical mediators that cause pain in acute inflammation.
Bradykinin and prostaglandins
Name the 5 local complications of acute inflammation.
Damage to normal tissue, tube obstruction, compression of structures/organs, loss of fluid (surface inflammation) and pain/loss of function
How do systemic outcomes of acute inflammation come about?
The inflammatory mediators in the bloodstream have systemic effects
Name the 4 systemic effects of acute inflammation.
Shock, fever, leukocytosis and acute phase response
How does acute inflammation result in fever?
Exogenous pyrogens stimulate macrophages to produce cytokines TNF and IL-1. They stimulate prostaglandin E2 synthesis in the hypothalamus which resets the body thermostat to a higher setting.
What is meant by leukocytosis and what chemical mediator induces it?
Leukocytosis refers to an increase the number of circulating lymphocytes.
Induced by colony stimulating factor produced by the macrophages and endothelial cells
What are the symptoms of acute phase response in acute inflammation?
Sleepiness, loss of appetite and raised pulse rate
What is the acute phase response and what stimulates it?
It is a change in the levels of some plasma proteins due to the liver changing its pattern of protein synthesis. Stimulated by inflammatory cytokines.
Which plasma proteins change their levels during the acute phase response?
Decreased albumin, increased fibrinogen, ceruloplasmi, C3, alpha1-antitrypsin and C reactive protein.
How does acute inflammation result in shock?
Dramatic systemic drop in blood pressure due to widespread vasodilation, increased vascular permeability and fluid Exudation.
Give the 3 outcomes of acute inflammation.
- Resolution
- Continued acute inflammation with chronic inflammation.
- Death
Name the 4 types of exudate.
Pus, Haemorrhagic, serous & Fibrinous
Why does pus exudate appear white?
Filled with neutrophils
When does exudate contain red blood cells?
Haemorrhagic - significant vascular damage due to destructive infection or malignant tumour
Describe serous exudate.
Clear in colour, contains many plasma proteins but few leukocytes. Occurs without infection (blisters).
What makes serous exudate different from plasma?
Contains fibrinogen
What makes serous exudate different from transudate?
Contains high levels of plasma proteins
Why can Fibrinous exudate be dangerous around the heart?
Can cause friction between the serosal surfaces of the pericardium and lead to pericarditis.
Give 6 clinical examples of acute inflammation.
Bacterial meningitis, lobar pneumonia, skin blisters, absesses, ascending cholangitis, acute appendicitis.
What are the 3 disorders of acute inflammation?
Hereditary angio-oedema, alpha1-antitrypsin deficiency and chronic Granulomatous disease
Hereditary angio-oedema is what?
A deficiency in C1-esterase inhibitor that stops spontaneous activation of the complement system.
Why does alpha1-antitrypsin deficiency cause liver disease?
Abnormal, unfolded protein produced in the liver that polymerise in the ER and can cause cirrhosis
What is chronic Granulomatous disease?
Phagocytes are unable to generate the superoxide free radical and so cannot kill phagocytosed bacteria
What are the 4 cell types principally involved with chronic inflammation?
- Lymphocytes
- Macrophages
- Fibroblasts
- Eosinophils
Which of the 4 symptoms of acute inflammation persist in chronic inflammation?
Swelling and pain
In what 3 ways can chronic inflammation arise?
- De Novo, without any preceding acute inflammation - due to autoimmunity, chronic infection or toxic agents.
- Take over from acute inflammation - e.g. In foreign body inflammation, necrotic tissue, antigen.
- Alongside acute inflammation - severe persistent irritation or ongoing bacterial infection
What might you expect to see under the microscope in chronic inflammation?
Mononuclear inflammatory cells (macrophages and lymphocytes) and granulation tissue
How long do macrophages survive in the blood?
About 6 days
Which out of neutrophils and macrophages is capable of replication?
Macrophages only
Name 4 functions of macrophages.
- Phagocytosis.
- Secretion of cytokines to summon other cells.
- Antigen presentation
- Stimulate acute phase reaction and fever
Give 4 functions of lymphocytes in chronic inflammation.
- Antigen processing and presentation.
- Antibody secretion
- Cytokine secretion
- Killing cells
Name 3 diseases in which eosinophils are commonly found.
- Worms
- Hodkin’s lymphoma
- Asthma in the bronchi
What is a giant cell?
Lots of macrophages fused together into one, multi-nucleated cell.
What type of inflammation are giant cells commonly seen in?
Granulomatous inflammation
Name the 3 types of giant cell.
- Langhans Giant Cells
- Foreign Body Giant Cells
- Toutan Giant Cells
Describe the appearance of Langhan’s giant cells.
Nuclei found round the periphery of the cell.
Name a disease that Langhan’s giant cells are famously associated with.
Tuberculosis
When are foreign-body giant cells seen?
What do they look like?
When there is a hard-to-digest foreign body present.
Nuclei are randomly arranged in the cell.
Describe the structure of a Toutan Giant Cell.
Nuclei in a ring in the centre of the cell with foamy cytoplasm surrounding.
Describe 2 situations where you might find Toutan Giant cells.
High lipid content lesions = xanthomas or fat necrosis
What does ‘fibrosis’ mean?
An excess of fibrous tissue
Why is collagen production important in chronic inflammation?
To wall of infected areas and fibrous scar production
Name 4 unwanted effects of chronic inflammation.
- Fibrosis
- Impaired function
- Atrophy
- Inappropriate immunological responses
Name 2 conditions where excess fibrosis in chronic inflammation impairs organ function.
Interstitial fibrosis of the lung
Cirrhosis of the liver
What is Granulomatous inflammation?
A type of chronic inflammation in which granulomas are seen
When is Granulomatous inflammation seen?
When the body is dealing with a particle that is difficult to eliminate - e.g. Thorns, splinters, mycobacteria
How large is a normal granuloma?
0.5-1mm
What is special about some of the macrophages in granulomas?
They have been modified into epitheloid cells - elongated, eosinophilic cytoplasm and tightly packed together
What is a granuloma?
A focal collection of inflammatory cells at a site of infection. Includes lymphocytes, macrophages, fibroblasts and epitheloid cells.
Name the 2 types of granuloma.
Foreign Body Granulomas & Immune Type Granulomas
What are the differences between foreign body and immune type granulomas?
- Foreign body granulomas tend to contain foreign body giant cells whereas immune type contain Langhans type giant cells.
- Foreign body granulomas contain very few lymphocytes
When do foreign body granulomas tend to form?
Around material that is not antigenic, e.g. Surgical thread, silicon or artificial joint breakdown
What is found at the centre of Immune Type Granulomas?
Caseous necrosis
When do Immune Type Granulomas form?
Around insoluble, antigenic particles - e.g. Syphilis, TB, leprosy, fungi, Sarcoidosis, Crohns
Define regeneration.
The proliferation of cells and tissues to replace dead, damaged or lost cells and structure with functional, differentiated cells.
What are labile cells?
Cells which in their normal state undergo active cell division so that they are continuously diving to replace cells that are destroyed.
Give 2 examples of labile cells.
Epithelial cells and haematopoietic cells.
Define stable cells.
Cell which in their normal state are resting in stage G0 of the cell cycle. They are not usually rapidly regenerating but can do in an appropriate stimulus.
Give 2 examples of stable cells.
Hepatocytes and smooth muscle cells.
What cell type (labile, stable or permanent) are osteoblasts And endothelial cells?
Stable
Name a type of epithelium that’s really stable cells rather than labile.
Renal tubular epithelium
Define permanent cells.
Cells that are unable to divide and regenerate as they cannot re-enter the cell cycle and undergo mitosis.
Give 3 examples of permanent cells.
Skeletal muscle cells, neurones and cardiac myocytes.
What is the role of stem cells?
They form an internal repair system to replace lost or damaged cells in tissues where terminally differentiated tissues cannot divide.
What is meant by stem cells having asymmetric proliferation?
One of the daughter cells remains as a stem cell and the other forms a specialised cell type.
What is a uni-potent stem cell?
A stem cell that can only produce one type of differentiated cell - lineage specific.
What is a multi potent stem cell?
A stem cell that can produce several types of differentiated cell.
Give an example of a multipotent stem cell found in the body.
A haematopoietic stem cell
Define a totipotent stem cell.
A stem cell that can produce any type of cell in the human body.
What is fibrous repair>
A response to injury that involves fibrosis / scar formation. Leading to altered structure unlike in resolution.
What 2 cell types / situations would fibrous healing occur in?
If there is cell death of permanent cell types OR if there is cell death in labile and stable cells with destruction of the collagen framework.
What are the 3 components to fibrous repair?
- Cell migration
- Angiogenesis
- Extracellular matrix production and remodelling
What are the 3 cell types involved in fibrous repair?
- Inflammatory cells
- Endothelial cells
- Fibroblasts
WHat is the function of endothelial cells in fibrous repair?
Stimulation of angiogenesis
What is the function of fibroblasts in fibrous repair?
Secretion of ECM proteins and myofibroblasts cause wound contraction
Why is angiogenesis important in fibrous repair of a healing wound?
Development of a blood supply to a healing wound provides access to inflammatory cells and fibroblasts and delivery of oxygen and nutrients to developing tissue.
What 2 cell types initiate angiogenesis and how?
Platelets and ECM secreting angiogenic cytokines in response to hypoxia
Describe the process of angiogenesis (5 stages).
- Endothelial proteolysis of basement membrane
- Endothelial migration via chemotaxis
- Endothelial proliferation
- Endothelial maturation and tubular remodelling.
- Recruitment of peri-endothelial cells.
Define angiogenesis.
The growth of new blood vessels from pre-existing vessels.
What are the roles oft he ECM during fibrous repair?
Supporting and anchoring of cells, separation of tissue compartments, sequestering of growth factors, communication between cells and cell migration.
What is granulation tissue?
A new connective tissue which is an intermediary replacement for normal dermis that will be remodelling into a scar.
What are the components of granulation tissue?
A dense network of microscopic blood vessels undergoing angiogenesis, inflammatory cells, endothelial cells and ECM (collagen) and fibroblasts.
Broadly, what are the 3 stages to fibrous repair / wound healing?
- Inflammation
- Proliferation
- Maturation
What occurs during the inflammation stage of wound healing?
Neutrophils phagocytosis necrotic tissue debris, blood clot forms. Inflammation may become chronic is macrophages and lymphocytes migrate in.
What is proliferating in the proliferation phase of wound healing?
Endothelial cells and fibroblasts
What replaces the blood clot in the proliferation phase of wound healing?
Granulation tissue due to angiogenesis and ECM production.
What is the maturation stage of wound healing / fibrous repair? What 3 things does it involve?
Cell population falls as ECM / collagen production increases and remodels. Granulation tissue matures into a fibrous scar - becoming less vascular. Myofibroblasts contract to reduce the volume of the defect.
Give 4 complications of fibrous repair / wound healing.
- Insufficient fibrosis
- Excessive fibrosis
- Excessive contraction
- Loss of function
What 3 pathologies can be caused by insufficient fibrosis?
Wound dehiscence, hernia, ulceration.
Give 4 patient conditions that make them more prone to insufficient fibrosis on wound healing.
Obesity, on steroids, malnourishment, elderly
Give 3 examples of excessive fibrosis.
Keloid scaring, cirrhosis and lung fibrosis in coal workers pneumonconiosis.
Give 2 pathologies involved with excessive wound contraction in wound healing.
Strictures
Contractures
Give an example of a situation where loss of function of a tissue is lost by wound healing.
In healed MI - replacement of specialised functional parenchymal cells with non-functioning collagenous scar tissue.
Give some less severe problems associated with fibrous repair / wound healing?
Restricted movement, loss of hair, itching, pain
What is the most common complication of wound healing?
Infection
How many collagens have been discovered so far?
27 types
Fibrillar collagens include…
Types I to III
Amorphous collagens include….
Types IV to VI
Which type of collagen is the most common in the body and where is it found?
Bones, tendons, ligaments, skin, sclera, cornea, blood vessels and hollow organs
On what 2 ions / vitamins is hydroxylation of the alpha chains of collagen dependent on?
Fe2+ and vitamin C
What enzymes remodel collagen fibres?
Collagenase S
Name 4 diseases caused by defects in collagen synthesis.
Scurvy, ehlers-danlos syndrome, osteogenesis imperfecta, Alpert syndrome
What is Scurvy?
A lack of vitamin C preventing the vitamin C dependent hydroxylation of alpha chains of tropocollagen so that tropocollagen lacks the strength formed by inter-chain hydrogen bonds and also becomes vulnerable to enzymatic degredation.
Give 3 symptoms of scurvy.
Haemorrhage, skeletal changes (weak bone) and longer wound healing.
What is Ehlers danlos syndrome caused by?
A deficiency in Lysyl oxidase - responsible for cross-linking of tropocollagen molecules.
Give 4 symptoms of Ehlers-Danlos syndrome.
- Stretchy, fragile skin
- Hyper-mobile joints
- Poor wound healing
- Colon and artery rupture
What is osteogenesis imperfecta?
Autosomal dominant genetic condition resulting in deficiency in type I collagen.
Give 4 symptoms of osteogenesis imperfecta.
Blue sclera, brittle bones prone to fracture, hearing impairment and dental abnormalities.
What is Alport syndrome?
An X-linked disease where there is a defect in type IV collagen synthesis - the type found in the basement membrane.
Give 3 symptoms of Alport Syndrome.
Deafness, kidney disease and damage to eye lens.
What are growth factors?
Extracellular signalling polypeptides coded for by proto-oncogenes that are transduced into a cell by receptor mediated signal transduction.
Give some examples of cell processes that growth factors control.
Proliferation, cell cycle gene expression, cell locomotion, contractility, differentiation, activation and angiogenesis
Give 4 examples of growth factors.
Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)
What 3 cell types secrete EGF?
Keratinocytes, macrophages and inflammatory cells
EGF is mitogenic for what cell types?
Epithelial cells, hepatocytes and fibroblasts.
Which type of granule is PDGF released in from the platelets?
Alpha granules
Name 5 cell types that might secrete PDGF.
PLatelets, macrophages, endothelial cells, smooth muscle cells and tumour cells
What does PDGF do?
Stimulates migration and proliferation of fibroblasts, smooth muscle cells and monocytes.
Which cell type is VEGF secreted from?
Endothelial cells
What is the major role of VEGF?
Angiogenesis and vasculogenesis stimulation
In terms of wound healing, what role does TNF play?
Induces fibroblast migration and proliferation and collagenase secretion.
Name 3 hormones important in wound healing.
Oestrogen, testosterone and growth hormone
Give 6 local factors that might delay wound healing.
Large wound, wound in an area with poor blood supply, infection, denervation of the region, lots of necrotic tissue present, large mechanical stresses on the area.
Give 7 patient-specific factors that can reduce wound healing / increase the time taken for a wound to heal
Elderly, certain drugs, dietary deficiency, immunocompromised, haemodynamic compromise (anaemia or hypovolaemia), obesity, malignancy
Name a drug class that might prolong wound healing time.
Steroids - anti-inflammatory so inhibit collagen synthesis
Give a class of drug that can speed up the wound healing process.
Antibiotics
What is it called when a surgical wound splits and give a risk factor for this.
Dehiscence - obesity is a risk factor
What is contact inhibition>
Contact of cells with the basement membrane or adjacent cells inhibits proliferation their proliferation. This allows normal, isolated cells to replicate until they form a mono layer of cells with no overlap.
Which 2 protein types in the cell membrane are important for regulation of contact inhibition?
Integrins - interact with the ECM
Cadherins- interact with other cells
= adhesion molecules
WHat is the role of contact inhibition in wound healing?
Re-epithelialisation in the proliferative stage of wound healing / fibrous repair is thought to be partly regulated by the loss of contact inhibition.
When would a wound heal by primary intention / Union?
In skin after an incised, uninfected wound with closely opposed edges (e.g. A surgical wound).
Name the 6 stages in primary intention wound healing.
- Haemostasis
- Inflammation
- Cell migration
- Regeneration
- Early scarring
- Scar maturation
What happens in the haemostat if phase of wound healing? How long does this take?
Severed arteries contract and the narrow space fills with clotted blood. The surface clot dehydrates forming a scab to seal the wound off from the environment and protect from infection.
Takes seconds to minutes.
What cell type appears in the wound area in the inflammation stage of primary intention?
Neutrophils at the wound margins
At what stage of wound healing does cell migration occur? How is this initiated?
Occurs about 48 hours after the wound occurred. Macrophages appear, scavenge dead neutrophils and become activated and begin secreting cytokines to attract fibroblasts and endothelial cells.
How fast do basal epidermal cells migrate over a wound during the cell migration phase of wound healing?
0.5mm/day
At what stage of primary intention does granulation tissue invade?
During regeneration (3 days after wound occurred)
What happens during the regeneration phase of primary intention?
Granulation tissue invades the wound area. Epithelial cell proliferation occurs to thicken the epidermal layer until the overlying scab falls off. Fibroblasts produce collagen and angiogenesis occurs.
When does early scarring of a wound occur?
7-10 days post wound
IN what direction does the epidermis regenerate in primary intention healing?
From superficial to deep epidermal layers
Give scenarios when secondary intention healing might occur.
After infarction, ulcer, absess, large wound, infected wound, many epithelial cells lost, edges of the wound not closely apposed.
Give 5 differences between primary and secondary intention wound healing.
- More granulation tissue in secondary intention.
- Larger clot with more necrotic debris in secondary intention.
- More inflammation occurs in secondary intention.
- In secondary intention, epidermis regenerates from superficial to deep.
- Wound contraction occurs in secondary intention.
- More substantial scar formation in secondary intention.
Give the 4 steps in fracture healing.
- Haematoma
- Soft/Pro Callus
- Hard callus
- Remodelling
Why is the formation of a haematoma in fracture healing important?
Provides a method for infiltration of macrophages, endothelial cells, fibroblasts, osteoblasts for formation of granulation tissue.
How are osteoblasts activated in fracture healing?
Macrophage infiltration followed by cytokine secretion which activates the osteoblasts.
What is the pro-callus stage of fracture repair?
Fibrous tissue and cartilage within which woven bone begins to form.
How is bone remodelled after fracture repair?
Mechanical stresses - that which is not stressed is resorbed by osteoclasts to re-establish the original shape of the bone.
Describe the healing process in a peripheral nerve.
Axonal degeneration (Wallerian degeneration) of distal segment = dies due to loss of blood supply and phagocytosed. Proximal segment sprouts and elongates using Schwann cells vacated by the distal segment to guide them back to the appropriate site.
How fast does the proximal portion of a severed peripheral nerve regrow?
1-3mm/day
Give a complication of peripheral nerve regeneration.
Neuroma
How does regeneration occur in the CNS?
Neurones are permanent tissue type so lost tissue replaced by glial cell proliferation
Why does cartilage not heal well?
Has no blood supply, lymphatic drainage or innervation
What is meant by haemostasis?
The physiological process that occurs to stop bleeding
What 4 things is haemostasis dependent on?
- Vessel wall
- Platelets
- Coagulation system
- Fibrinolytic system
How does the vessel wall play a role in haemostasis?
It can constrict to limit blood loss
What is a platelet and from what is it derived?
A subcelluar fragment derived from megakaryocytes
What are the 2 roles of platelets in haemostasis?
- Adhere to each other and the damaged vessel to form a platelet plug via Von Willebrand factor
- Undergo the platelet release reaction where molecules are released to expand the plug and activate the coagulation system
What 2 types of platelet granules are there?
Alpha and dense granules
Name 5 molecules that are found in the alpha granules of platelets.
- PDGF
- Fibrinogen
- Fibrionectin
- Platelet factor 3
- Cationic proteins
Name 5 molecules that are found in dense granules of platelets.
Ca2+, serotonin, histamine, adrenaline, ADP
Name a potent platelet aggregating agent that causes secondary aggregation.
ADP
How will the stability of the initial platelet plug be increased?
Addition of fibrin, thromboxane and thrombin
What initiates the intrinsic pathway of the coagulation system?
Damage to the endothelium
Describe the stages of the intrinsic pathway of the coagulation system?
Factor 12 –> Factor 12a –> Factor 11 –> Factor 11a –> Factor 9 –> Factor 9a –> Factor 10 –> Factor 10a –> Prothrombin –> Thrombin –> Fibrinogen –> Fibrin
What initiates the activation of the extrinsic pathway of the coagulation system?
Trauma
Describe the pathway of the extrinsic pathway of the coagulation system.
Factor 7 –> Factor 7a –> Factor 10 –> Factor 10a in a tissue-factor dependent process.
Name 5 naturally occurring thrombin inhibitors.
Anti-thrombin III, alpha1 anti-trypsin, alpha2 macroglobulin, protein C, protein S.
What is thrombophilia and what might cause it?
A condition where thrombus formation is common in unexpected places. Can be caused by a deficiency in anti-thrombin or protein C or protein S (thrombin inhibitors).
Describe the fibrinolytic pathway.
Plasminogen is converted to plasmin by plasminogen activators, plasmin is a protease that breaks down fibrin clots into fibrin degradation products.
What is the target of Heparin and therefore what is it used for?
It is an activator of antithrombin III which is a protease that inactivates thrombin and other clotting factors. Therefore used to prevent thrombus formation in high risk patients “thins the blood”.
Name 2 molecules that are given therapeutically to activate the fibrinolytic system. What effect will this have?
Plasminogen activators such as tPA (tissue plasminogen activator) & streptokinase.
Cause production of active plasmin which is a protease that breaks down fibrin clots into fibrin degradation products = anti-thrombotic.
Name 4 molecules that are produced by the endothelium that are anti-thrombotic.
Plasminogen activators (e.g. tPA = tissue plasminogen activator), prostacyclin, nitric oxide and thrombomodulin
Define thrombosis.
The formation of a solid mass of blood within the circulatory system during life.
According to Virchow’s Triad, what are the 3 disposing factors to thrombosis?
Haemodynamic changes (flow changes), endothelial injury (vessel wall changes), hypercoagulability (blood constituent changes)
Name 2 haemodynamic changes that are pro-thrombotic.
Stagnation and turbulent blood flow
Give 3 changes in the vessel wall that might be pro-thrombotic.
Atheroma, direct injury or inflammation of the endothelium
Give 3 situations when patients are in a hyper-coagulative state.
Post-partum or during pregnancy, smokers and post-operative
What are the main 2 consequences of an arterial thrombus?
Ischaemia and infarction
Define infarction.
Tissue death due to a local lack of oxygen (Ischaemia).
Give 3 macroscopic features of an arterial thrombus.
Pale, granular with lines of Zahn
Why is an arterial thrombus darker in the middle but paler at the periphery?
Darker in the middle where red blood cells were present and paler at the edges where there is lots of fibrin present.
Name 4 outcomes of a venous thrombus.
Congestion, oedema, ischaemia, infarction
If a patient presents with oedema, is an arterial or venous thrombus likely to be present and why?
Venous because causes congestion and raises hydrostatic pressure of the vessel causing more tissue fluid to be forced out.
Describe the macroscopic features of a venous thrombus.
Softer, gelatinous, dark red
Why are venous thrombi darker in colour than arterial?
Because venous thrombi have a higher cell content
Describe the process of propagation in thrombus formation.
A small thrombus becomes larger and can obstruct more vessels as more platelets and erythrocytes and fibrin accumulate.
In which direction does the tail end of a venous thrombus extend?
Therefore, in what direction does a venous thrombus propagate?
In the direction of blood flow - towards the heart.
Propagates in the proximal direction, blocking larger veins.
In what direction does the tail end of an arterial thrombus grow and propagate?
Also towards the heart - in retrograde direction
Apart from dissolution/resolution, what are the other 3 possible fates of a thrombus?
Organisation, recanalisation or embolism
How does a thrombus undergo dissolution?
The fibrinolytic system is active
What is meant by organisation of a thrombus?
Ingrowth of fibroblasts and capillaries into the thrombus so it becomes more similar to connective tissue. However the lumen remains blocked.
What is meant by recanalisation of a thrombus?
One or more channels form through the thrombus to re-establish blood flow through the vessel, although this is incompletely.
How can embolism result from a thrombus?
Part of the thrombus breaks off and travels in the bloodstream to become lodged at a distant site.
Define an embolism.
Blockage of a blood vessel by a solid, liquid or gas at a site distant from its origin.
What percentage of emboli are thrombo-emboli?
90%
Apart from thrombi, give 7 other substances that can be the cause of an embolism.
Air, amniotic fluid, nitrogen, medical equipment, tumour cells, cholesterol, fat
What is fat embolism commonly a complication of?
A bone fracture
If you have a thrombus in the systemic veins, where is it most likely to embolise to?
The lungs
If you have a thrombus forming in the heart, where is it likely to embolise to?
Renal or mesenteric arteries via the aorta
If you have a thrombus formation in the carotid artery, where is it likely to embolise to?
The brain
Where is an abdominal aorta thrombus likely to embolise to?
The legs
What is the classical appearance of a brain embolism?
Wedge-shaped infarct.
Name 5 factors that might pre-dispose an individual to deep vein thrombosis as a result of hyper-coaguability.
Post partum/pregnancy, disseminated cancer, severe burns, oral contraceptives, post-operative
Give 2 factors that might predispose an individual to deep vein thrombosis as a result of haemodynamic changes.
Immobility / bed rest and cardiac failure
What reduction in blood flow will be fatal in a pulmonary embolism?
60%
What are the symptoms of someone suffering a minor pulmonary embolism?
Few symptoms but may be some shortness of breath, and if recurrent small pulmonary embolisms occur then pulmonary hypertension may arise
WHat are the symptoms of a major pulmonary embolism?
Coughing, shortness of breath, blood-stained sputum
Give 2 ways by which thrombosis is prevented in susceptible patients.
Treatment with sub-cutaneous heparin and massage of legs during surgery.
Give 2 drugs which are used to treat individuals who present with thrombosis.
Warfarin and heparin
What is the mechanism of action of warfarin?
Suppresses the vitamin-K dependent synthesis of clotting factors
Why is aspirin given to patients with coagulation disorders?
Irreversible inactivation of the COX enzyme that is required for thromboxane A2 synthesis which prevents platelet aggregation for the whole lifetime of the platelet.
Why is streptokinase given in prevention of thrombosis?
a thrombolytic drug that activates plasminogen to form active plasmin - a protease that degrades the fibrin clots into fibrin degredation products
Define atheroma.
Accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries.
Define atherosclerosis.
Thickening and hardening of arterial walls as a consequence of atheroma.
Define arteriosclerosis.
Thickening of the walls of smaller arteries and arterioles as a result of hypertension and diabetes Mellitus.
What are the 3 macroscopic stages of atheroma?
- Fatty streak
- Simple plaque
- Complicated plaque
What causes a fatty streak?
Lipid deposition in the blood vessel intima
Describe the appearance of a fatty streak.
Yellow and slightly raised from the intima.
What does a simple plaque look like?
Raised yellow/white region with irregular outline. Widely distributed.
How would you distinguish a complicated plaque in atheroma?
Has thrombosis on the surface and haemorrhage into the plaque. Becomes calcified.
A complicated plaque is likely to cause the vessel to do what?
Aneurysm - localised bulging due to weak vessel wall
What are the early microscopic changes in an atheroma plaque?
- Smooth muscle cell proliferation
- Foam cell accumulation
- Extracellular lipid accumulation
What microscopic changes might you see in a late atheroma plaque? (8 in total)
Fibrosis Necrosis Cholesterol crystals Inflammatory cells Disrupted of internal elastic lamina --> extension into the media. Blood vessels grow into the plaque. Plaque fissuring.
From internal to external, what are the 5 layers of a blood vessel wall?
- Tunica intima
- Internal elastic lamina
- Tunica media
- External elastic lamina
- Tunica adventitia
Name 5 ‘organs’ or ‘areas’ that atheroma commonly affects.
Heart, brain, legs, GI tract, aorta
Name 6 types of artery commonly affected by atheroma.
Aorta, coronary arteries, carotid arteries, cerebral arteries, leg arteries, mesenteric arteries
Which part of the aorta is most commonly affected by atheroma?
Abdominal
What is the consequence of aortic atheroma?
Abdominal Aortic Aneurysm (AAA)
Give 4 consequences of atheroma in the coronary arteries. What is the umbrella term for this?
MI, angina, arrhythmias, cardiac failure.
Caused by Ischaemic heart disease.
Atheroma in the cerebral or carotid arteries causes what?
Cerebral ischaemia
On an image of a dissected heart, how might you tell the difference between a recent and previous myocardial infarction?
Recent will be darker in colour - very red.
Previous infarct will be white scar tissue.
What are the 3 possible consequences of cerebral ischaemia as a result of carotid or cerebral atheroma?
- Transient ischaemia attack
- Cerebral infarction (stroke)
- Multi-infarct dementia
What is the difference in the usual causes of stroke (cerebral infarct) versus multi-infarct dementia?
Stroke is usually caused by an embolus from the carotid arteries.
Multi-infarct dementia more likely to be caused by atheroma of the vessels themselves.
What type of infarct do you see in stroke?
Red / Haemorrhagic infarct
What consequences might occur due to atheroma in the mesenteric arteries?
Ischaemic colitis (most common type of bowel ischaemia)
Malabsorption.
Intestinal infarction.
What are the 4 possible complications that result from atheroma in the leg arteries?
What is the umbrella term for these?
- Intermittent claudication
- Leriche syndrome
- Ischaemic rest pain
- Gangrene
All types of peripheral vascular disease
What is meant by intermittent claudication?
Pain in the legs after walking due to reduced blood supply. Time taken to cause pain might decrease over time.
What is leriche syndrome?
Aortoiliac occlusive disease –> blockage of the aorta as it branches into iliacs. Results in claudication, decreased femoral pulse, erectile dysfunction and incontinence.
List 10 risk factors for atheroma.
Age Gender Hyperlipidaemia ApoE genotype Smoking Familial hyperlipidaemia Hypertension Diabetes Mellitus Alcohol Infection
Which sex is more prone to atheroma? Why is this thought to be?
Men are more prone until after menopausal age of women, thought to have a hormonal basis.
Give 3 symptoms of familial hyperlipidaemia. What is the major concern with having this disease?
Corneal arcus, xanthalasma and xanthomas.
Likely to lead to early development of atheroma.
What are the proposed mechanisms by which smoking may increase risk of atheroma?
Causes hypercoagulability.
Reduced prostaglandin production - a vasodilator.
What is the possible mechanism by which hypertension causes atheroma?
Damages the endothelium
How many units of alcohol per day is associated with increased risk of Ischaemic heart disease?
More than 5 units per day
Name 3 microorganisms (infectious agents) that are thought to be associated with atheroma.
Chlamydia pneumoniae.
Helicobacter pylori.
Cytomegalovirus.
Name 5 other risk factors that show some relationship with atheroma.
Oral contraceptives. Obesity. Soft water. Lack of exercise. Stress - personality type.
The genetic predisposition to atheroma is thought to be due to:
Variations in apolipoprotein metabolism.
Variations in apolipoprotein receptors.
What are the 4 theories of atheroma Pathogenesis?
- Thrombogenic hypothesis
- Insudation hypothesis.
- Monoclonal hypothesis
- Reaction to injury hypothesis.
Explain the thrombogenic theory of atheroma formation.
Plaques are formed by repeated thrombi, and the lipid is derived from these thrombi. Fibrous tissue grew over the lipid.
Explain the insudation theory of atheroma.
Endothelial injury results in inflammation and increased permeability of the vessel wall to lipid in the plasma.
Describe the monoclonal hypothesis of atheroma.
Smooth muscle cells the key cell type. Each plaque formed of monoclonal smooth muscle cells with possible abnormal growth control. Potentially thought each plaque to be a benign tumour.
Explain the reaction to injury hypothesis of atheroma.
Plaques form in response to endothelial injury which increases permeability and allows platelet adhesion. Monocytes penetrate the endothelial wall to form macrophages. Smooth muscle cells proliferate and migrate.
In the reaction to injury hypothesis, what is a potential cause of the endothelial injury?
Oxidised lipids
What are the 4 stages of the unifying hypothesis of atheroma?
- Endothelial injury
- Platelet adhesion & lipid accumulation
- Secretion
- Neovascularisation
What are the 4 potential causes of endothelial injury in the unifying hypothesis of atheroma?
Raised LDL, toxins, hypertension, haemodynamic stress
What stimulates smooth muscle cell proliferation and migration in stage of 2 of the unifying hypothesis of atheroma?
Platelet adhesion leading to PDGF released acting on the smooth muscle cells
What occurs in the lipid accumulation part of stage 2 of the unifying hypothesis of atheroma?
Lipid insudates and is oxidised. Taken up by smooth muscle cells and macrophages that have migrated into the lamina from the blood (monocytes).
What is secreted in the ‘secretion’ stage of the unifying hypothesis of atheroma?
Extracellular matrix by the smooth muscle cells.
Cytokines from the foam cells.
What is the outcome of foam cell cytokine secretion in the 3rd stage of the unifying hypothesis of atheroma?
Smooth muscle cells are further stimulated to proliferate, migrate and secrete matrix, and more inflammatory are recruited.
What 6 cell types are key players in atheroma?
Endothelial cells, platelets, smooth muscle cells, macrophages, lymphocytes and neutrophils
What 3 roles do endothelial cells okay in atheroma?
Altered permeability to lipoproteins.
Collagen production.
Stimulate smooth muscle cell proliferation and migration.
What is the major role of platelets in atheroma?
Stimulation of proliferation and migration of smooth muscle cells by secretion of PDGF
What are the 2 major roles of smooth muscle cells in atheroma?
Take up lipid to Dom foam cells.
Secrete collagen and proteoglycans (matrix).
What 4 roles do macrophages play in atheroma?
LDL oxidation.
Take up lipid to form foam cells.
Secrete proteases which remodel matrix.
Stimulate smooth muscle cell proliferation and migration.
What is the role of lymphocytes in atheroma?
Secretion of TNF which may alter lipid metabolism and stimulate proliferation and migration of smooth muscle cells.
What is the role of neutrophils in atheroma?
Protease secretion to cause local damage and inflammation
By what 6 methods might you prevent atheroma?
Stop smoking. Decrease fat intake. Treat hypertension. Decrease alcohol intake. Exercise regularly. Control weight.
What 5 interventions are used once atheroma has developed?
Stopping smoking. Diet modification. Hypertension treatments. Diabetes treatments. Lipid lowering drugs (statins)
Define regeneration.
Replacement of cell losses by identical cells in order to maintain the original size of a tissue or organ.
Give examples of 3 tissue types that can undergo regeneration.
Epithelium, liver and bone marrow
What induces regeneration?
Growth factors, cell to cell communications or electrical currents
Define hyperplasia.
An increase in tissue or organ size due to increased cell numbers in response to increased functional demand and/or external stimulation.
What tissue types can undergo hyperplasia?
Labile and stable cell populations only
Give 2 examples of where hyperplasia occurs physiologically.
- increased bone marrow production of erythrocytes in response to low oxygen.
- proliferation of the endometrium under the influence of oestrogen
What stimulates hyperplasia when it occurs physiologically?
Hormones
Give 2 examples where hyperplasia occurs in pathological conditions.
- epidermal thickening in eczema and psoriasis
- enlargement / goitre of thyroid gland in iodine deficiency
What causes hyperplasia to occur in pathological conditions?
Excessive hormone or growth factor production
Why might hyperplasia put you at risk of neoplasia?
Repeated cell divisions increase risk of mutation
Can hyperplasia be under pathological control?
No. Always a physiological response.
Define hypertrophy.
An increase in tissue or organ size due to an increase in cell size without increasing cell numbers. Cells contain more structural components in response to increase functional demand or hormonal stimulation.
What cell type most commonly undergoes hypertrophy.
Permanent cells
Give 6 examples of hypertrophy under physiological conditions.
- Skeletal muscle hypertrophy in body builders.
- Smooth muscle hypertrophy in uterus during pregnancy.
- Cardiac muscle hypertrophy in athletes.
- Compensatory hypertrophy of kidney after removal of the other.
- Adipose cell hypertrophyin excessive nutrition.
Give 3 examples of when hypertrophy occurs in pathological conditions.
- cardiac muscle hypertrophy in systemic hypertension of valve disease
- Smooth muscle hypertrophy above intestinal stenosis
- smooth muscle hypertrophy in bladder due to enlarged prostate gland (obstruction)
Define atrophy.
Shrinkage of a tissue or organ due to an acquired decrease in cell size and/or number following a reduced supply of growth factors or nutrients.
What cell types can undergo atrophy?
Any
Give 2 examples where atrophy occurs in a physiological situation.
- ovarian atrophy after menopause
- uterus atrophy after parturition
Give 12 causes of atrophy.
Disuse. Denervation. Inadequate blood supply. Inadequate nutrition. Loss of endocrine stimulation. Persistent injury. Senile. Pressure on tissue. Occlusion of tissue. Toxic agents and drugs. X-Rays. Immunological mechanisms.
What type of cell adaptation is osteoporosis the result of?
Atrophy - of bone mass.
What type of cell adaptation is male baldness? Which cell type does it effect?
Atrophy of hair follicles
Give an example where atrophy might occur due to disuse.
Atrophy of skeletal muscle after immobilisation in a plaster case.
Give an example of where atrophy might occur due to denervation.
In the thenar muscles of the hand following median nerve injury.
Give an example of where atrophy occurs due to inadequate blood supply.
In skin of the legs with peripheral vascular disease
When would inadequate blood supply cause atrophy rather than ischaemia?
If the loss of blood supply is only partial, but is prelonged.
Give an example of where atrophy occurs following inadequate nutrition.
Adipocyte atrophy in malnutrition.
Give an example where atrophy might occur following loss of endocrine stimulation.
Atrophy of breast, reproductive organs and adrenal gland following hypophysectomy (removal of pituitary gland).
What tissues tend to be affected by senile atrophy?
Brain, heart, liver, kidney, spleen
Give 2 examples of atrophy as the result of pressure on a tissue.
Cerebral atrophy adjacent to a meningioma.
Thoracic wall atrophy adjacent to a thoracic aortic aneurysm.
Give an example of where atrophy might occur due to occlusion of a tissue.
Blockage of main pancreatic duct causes disappearance of exocrine glands.
What is pernicious anaemia? What does it amuse atrophy of?
Pernicious anaemia = anaemia because of the inability to absorb vitamin B12 for erythrocytes production.
Can result from immunological destruction (autoantibodies) of the parietal cells in the stomach.
During tissue atrophy, which cell types are lost first?
Parenchymal cells lost first - leaving behind stroma / connective tissue
What is the mechanism by which cells undergo atrophy?
Self digestion involving ubiquitin
At what point does atrophy become irreversible?
Once all parenchymal cells are replaced by connective tissue.
What is the likely cause of senile atrophy?
Accumulation of somatic mutations in the cell
What is the likely cause of pressure atrophy?
Ischaemia of the compressed tissue
Define metaplasia.
The reversible replacement of one adult differentiated cell type by another of a different type.
What cell types undergo metaplasia?
Those that can divide - epithelium
What is the most common metaplastic change?
Columnar to squamous epithelium
Give 2 examples of where metaplasia occurs in physiological conditions.
Myeloid metaplasia - bone marrow destruction so metaplasia of spleen to bone marrow.
Columnar to squamous epithelium in exocrine ducts due to chronic irritation from stones.
What type of metaplasia is caused by cigarrette smoke and where? Why is this pathological?
Bronchial pseudostratified ciliated columnar epithelium to stratified squamous.
Lack cilia and mucous production.
What type of metaplasia occurs in Barrett’s oesophagus? Where does this occur and why?
Stratified squamous epithelium to secretory gastric columnar epithelium.
Occurs in lower oesophagus due to persistent acid reflux.
What type of metaplasia occurs in traumatic myositis ossificans? What is the most common cause?
Metaplastic bone development in skeletal muscle following trauma when young people return to activity before healing.
Fibroblast metaplasia to osteoblasts.
Metaplasia does not occur across…
Germ layers
What is the difference between metaplastic and dysplastic cells?
Metaplastic cells are fully differentiated
What is the difference between hyperplasia, hypertrophy, atrophy and metaplasia with neoplasia?
They are reversible
What determines whether a cell undergoes injury / necrosis or adaptation?
How severe the challenge is
Define reconstitution.
Replacement of a lost body part requiring co-ordinated regeneration of several cell types.
Give 5 examples of reconstitution (not necessarily in humans).
Lizards tail regrowth Regrowth of deer antlers Small blood vessels Distal phalange of a child less than 4.5 years Holes in ears of cats and rabbits
Define aplasia.
The complete failure of a tissue or organ to develop.
Give 2 examples of asplasia.
Thymus asplasia in embryology
Bone marrow asplasia in aplastic anaemia
Define Involution.
Normal, programmed shrinkage of an organ
How does Involution differ with atrophy?
Atrophy tends to be pathogenic whereas Involution is physiological
Give an example of Involution.
Thymus involution in early life.
Define hypoplasia.
Congenital underdevelopment of an organ or tissue.
Give 2 examples of hypoplasia.
Testicular hypoplasia in Klinefelters syndrome.
Hypoplastic heart - abnormal chambers.
Define atresia.
Congenital imperforation of an opening.
In what tissues can atresia develop?
Anus, vagina or pulmonary valve
Define dysplasia.
Abnormal maturation of cells within a tissue so that cells have disorganised and abnormal differentiation.
What is the difference between dysplasia and neoplasia?
Dysplasia is reversible
Give 2 cell adaptations that often prelude neoplasia.
Metaplasia and dysplasia.
What is intracrine signalling?
A type of autocrine signalling where a cell synthesises a factor that has an effect by binding intracellular receptors without being secreted.
Growth factors are what type of molecule?
Polypeptides
What type of teens encode growth factors?
Proto oncogenes
Give 7 functions of growth factors.
Stimulate cell proliferation, locomotion, contractility, differentiation, viability, activation and angiogenesis.
What is the function of granulocyte colony stimulating factor? Therefore, what can it be used for?
Stimulates bone marrow to produce granulocytes, especially neutrophils, and release them into the blood.
Used to stimulate poorly functioning bone marrow - e.g. In chemotherapy.
How does increased growth of a tissue occur?
- Shorten cell cycle
2. Conversion of quiescent cells in G0 to proliferating cells by entering cell cycle
What is the restriction point in the cell cycle and where is it located?
A checkpoint for damaged DNA at the end of G1.
What happens if a cell fails to get past the restriction point?
P53 suspends the cell cycle and triggers DNA repair mechanisms. If these are unsuccessful, then apoptosis.
Where in the cell cycle are check points located?
End of G1 = restriction point
G1/S transition
G2/M transition
What type of protein regulates progression through the cell cycle?
Cyclins and cyclin-dependent kinases.
CDKs become active on binding cyclins and regulate the cell cycle by phosphorylation proteins.
The activity of cyclin-CDK complexes is regulated by….
CDK inhibitors
True or false: permanent cells do not have any stem cells.
False. They can have them - but cannot mount an effective proliferative response
True or false: labile cell population mature differentiated cells can replicate.
False - regeneration done by stem cells
In which cell type are the mature, differentiated cells involved in proliferation, in addition to stem cells?
Stable cell populations - liver and kidney
Give 4 tissue types with good regenerative capacity.
Bone, liver, smooth muscle, epithelium
Name 2 tissue types with poor regenerative capacity.
Tendons and cartilage
Name 2 cell types with no regenerative capacity.
Adipocytes and central nervous system
Mesothelium has what kind of regenerative capacity?
Good
What is the problem with the regenerative capacity of melanocytes?
Tend to regenerate too much or too little
Skeletal muscle has what kind of regenerative capacity?
Limited
Why is secondary rupture of a tendon common?
Heal slowly as have poor regenerative capacity. Due to few cells and few blood vessels.
Give 2 types of epithelia that are exceptions, and do not proliferate well.
Renal podocytes and lens of the eye
Regeneration of skeletal muscle comes from what kind of cell?
Satellite cells
How fast will a sprouting axon grow after peripheral nerve damage?
1-3mm/day
How does an amputation neuroma develop?
Following loss of a peripheral nerve that requires regeneration but the gap the axon must cross is too wide - form a disordered tangle.
How do people with hemiplegia following stroke recover if the CNS cannot regenerate?
CNS establishes alternative pathways = plasticity
What can cell adaptation be thought of a state between?
A normal unstressed cell, and a stressed injured cell
Give an example of when slow maturity in regenerating cells in beneficial.
In flu virus. Will kill mature epithelial cells of the upper respiratory tract but spares regenerating cells as they do not express the receptors for influenza virus yet.
The longer the maximum lifespan of a species the ***** cell divisions can occur.
More
What is the Hayflick number?
The number of divisions a cell can do.
What is the Hayflick number in humans?
61.3
What is the advantage in a cell becoming hypertrophied?
Cell contains more structural components so that cellular workload is shared by a greater mass of cell components.
Why is fibrosis commonly seen in hypertrophic hearts?
Not an increase in capillaries or arteries to sufficiently satisfy the increase in muscle mass - cause anoxia.
Tissue atrophy is due to a combination of:
Cell atrophy and cell apoptosis
What is seen inside cells undergoing atrophy by cell shrinkage?
Residual bodies - autophagosomes containing lipofuscin and remains of organelles that cannot be further digested
Which organ is least susceptible to starvation induced atrophy?
The brain
How does metaplasia occur?
Stem cells within the tissue are reprogrammed and switch to producing a different kind of progeny.