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77 Cards in this Set
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Define regeneration and associated cell types.
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Regeneration is the replacement of dead or damaged cells by functional, differentiated cells. Differentiated cells are derived from stem cells.
1. Labile cells eg epithelial or haemopoietic cells - Normal state is active cell division - Usually rapid proliferation 2. Stable cells eg hepatocytes, osteoblasts, fibroblasts - Not normally dividing at a significant rate - Variable speed of regeneration 3. Permanent cells eg neurone, cardiac myocytes - Unable to divide - Unable to regenerate |
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Describe stem cells.
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- Stems cells have ability of potential limitless proliferation
- Daughter cells either remain as stem cells to maintain the stem cell pool OR differentiate to a specialised cell type. - In early life stem cells develop into many different cell types. - Internal repair system to replace lost or damaged cells in tissue - Therapeutic utility in degenerative disease. |
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Define unipotent, multipotent and totipotent.
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Unipotent – can only produce one type of differentiated cell eg epithelia
Multipotent – can produce several types of differentiated cell eg haemopoetic Totipotent – can produce any type of cell ie embryonic stem cells |
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Describe the mediators and factors controlling regeneration.
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1. Growth factors – promote proliferation in the stem cell population eg EGF, FGF, PDGF
2. Hormones eg ACTH, oestrogen 3. Contact between basement membranes and adjacent cells inhibits proliferation – contact inhibition. - Cancer inhibits proliferation of contact tissues and so loss of contact inhibition promotes proliferation. Regeneration cannot occur in permanent cells and only in stabile and labile cells if tissue framework is retained. |
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Describe fibrous repair and the mechanisms and cells involved and how it is controlled.
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Fibrous repair is the replacement of functional tissue by scar tissue.
Key mechanisms: 1. Cell migration Inflammatory cells: recruited by chemotaxis for phagocytosis of debris by macrophages and neutrophils and recruitment of chemical mediators eg lymphocytes and macrophages. 2. Angiogenesis Endothelial cells – angiogenic cytokines eg VEGF 3. Extracellular matrix production and remodelling Fibroblasts/myofibroblasts – for collagen synthesis, wound contraction. Recruited by pro fibrotic cytokines eg PDGF, FGF, TGF-beta produced from macrophages |
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Describe the functions of angiogenesis and how it occurs.
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Adequate blood supply is vital to wound healing
- Provides access to the wound for inflammatory cells and fibroblasts - Delivery of oxygen and other nutrients 1. Endothelial proteolysis of basement membrane 2. Migration of endothelial cell via chemotaxis 3. Endothelial proliferation – loss of contact inhibition and induced by VEGF 4. Endothelial proliferation, maturation and tubular remodelling 5. Recruitment of periendothelial cells These mechanisms are deranged in tumour cells! |
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Describe the function of the extracellular matrix and the components.
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Function
1. Supports and anchors cells 2. Separates tissue compartments eg basement membrane 3. Sequesters growth factors 4. Allows communication between cells 5. Facilitates cell migration eg of endothelial cells Components: Collagen – vital for structural integrity - Type 1- bone, tendon, scars - Type III – tissue scaffold - Type IV –non fibrous, basement membranes Glycoproteins - Organises and orientate cells, support cell migration - Fibronectin, laminin tenascin Proteoglycans - Matrix organisation, cell support, regulate availability of growth factors - Heparin sulphate proteoglycan Elastin - Provides tissue elasticity. |
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Describe collagen synthesis.
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1. During translation of pre-pro collagen in the cytoplasm, a signal receptor particle that recognises a signal sequence on the protein binds to it.
2. Translation is halted and the protein, ribosome and signal particle complex is translocated to the cytoplasmic ER surface, powered by GTP bound to SRP, where it binds to a docker protein –SRP receptor. 3. The SRP is released and translation continues via an open pore- peptide translocation complex, into the ER lumen. 4. Pre pro collagen is synthesised and the ribosome dissociates from the ER 5. The signal sequence is cleaved by signal peptidase on the luminal surface of ER. 6. hydroxylation of lyseine and proline residues using vitamin C 7. N linked glycoslyation of amino acid side chains of asparagines 8. Galactose is added to hydroxylyseine residues 9. 3 alpha peptides align and from triple helix with disulphide bonds between them 10. Pro-collagen is released in a vesicle to the cis surface of golgi apparatus . 11. O linked glycosylation of OH groups on ser and thr. 12. Exocytosis of pro-collagen 13. End sequences are cleaved in extracellular matrix to form tropocollagen molecules 14. Lateral association of tropocollagen molecules by covalent bond cross links between lyseine residues forms a fibril 15. Aggregations of fibrils forms a fibre. Fibres are relatively resistance to general proteases, slow remodelling by specific collagenases. |
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Describe the detailed steps of fibrous repair – inflammatory cell infiltrate, formation of granulation tissue and maturation.
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Inflammatory cell infiltrate:
1. Blood clot forms 2. Acute inflammation around the edges – neutrophils infiltrate and digest clot 3. Chronic inflammation – macrophages and lymphocytes migrate into the clot Formation of granulation tissue 4. Angiogenesis – capillaries and lymphatics sprout and infiltrate 5. Myofibroblasts migrate and differentiate to make glycoproteins 6. Extracellular matrix is produced - vascular network, collagen synthesised, macrophages reduced Maturation 7. Cell population falls 8. Collagen increases, matures and remodels – collagenases 9. Vessels differentiate are reduced 10. Myofibroblasts contract – reduce volume of defect 11. Left with fibrous scar |
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Describe how platelets are activated to form blood clot.
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Platelets are activated when brought into contact with:
- collagen (which is exposed when the endothelial blood vessel lining is damaged) - thrombin (primarily through PAR-1) - ADP receptors (P2Y1 and P2Y12) expressed on platelets - A negatively charged surface (e.g. glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors. Extrinsic pathway: coagulation is initiated by a substance generated from damaged tissues called Tissue Factor by interaction with factor VII Intrinsic Pathway: coagulation is initiated by contact with surface agents such as collagen or by proteases such as kallikrein, acting through factor XII |
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Describe healing of a clean incised skin wound.
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A clean incised skin wound can be healed by primary intention – suture.
- Well apposed edges - sutured - Minimal clot and granulation tissue - Epidermis regenerates due to loss of contact inhibition - Dermis undergoes fibrous repair - Sutures out at 5-10 days - Maturation of scar continues up to 2 years - Minimal scarring, good strength - Risk of trapping infection – abscess, inflammation – further tissue damage |
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Describe healing of a large skin defect.
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Healing of a large skin wound is by secondary intention.
- Unopposed would edges - Clot dries to form a scab or eschar - Epidermis regenerates beneath from basal layer. - Much more granulation tissue is produced. |
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Define granulation tissue
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Granulation tissue is perfused, fibrous connective tissue that replaces a fibrin clot in wound healing. It has various functions: extracellular matrix, immune function, angiogenesis.
Compare healing by secondary and primary intention. Secondary intention - Takes longer - Produces a larger scar, not necessarily weaker - Produces more late contraction to reduce volume of defect. |
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Describe factors influencing wound healing
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Local factors
1. Type , size ( large wound takes longer to heal), location of wound 2. Apposition, lack of movement – bone fractures, severed nerves 3. Blood supply – arterial, venous 4. Infection – suppuration, gangrene, systemic 5. Foreign material – dirt, glass, sutures, necrotic tissue 6. Radiation damage General factors 1. Age –older people don’t repair as well 2. Drugs and hormones 3. General dietary deficiencies eg protein 4. Specific dietary deficiencies - Scurvy – vitamin c – alpha chain hydroxylation - Essential amino acids 5. General state of health - Chronic diseases eg diabetes, rheumatoid arthritis 6. General cardiovascular status |
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Describe some complications of fibrous repair.
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Insufficient fibrosis
- Wound dehiscence – rupture of wound alongside sutures - Hernia - Ulceration Caused by obesity, elderly, malnutrition, steroids. Excessive fibrosis - Cosmetric scarring - Keloid - Cirrhosis – along with nodules of regenerated liver cells -> distortion of liver architecture -> portal hypertension - Lung fibrosis Excessive contraction - Contractures – limitation of joint movement – physiotherapy could help/ skin grafts - Strictures – narrowing of tubes and channels causing obstruction |
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Describe the pathways of the reparative response
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INJURY -> INFLAMATION
INFLAMATION -> NECROSIS or NO NECROSIS NO NECROSIS - Exudate resolved -> normal structure – resolution - Exudates organised -> scarring NECROSIS - Tissue of permanent cell -> scarring - Tissue of stable or labile cell - if framework is intact -> regeneration and resolution is possible BUT if framework is destroyed -> scarring |
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Describe the healing in cardiac muscle and brain.
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Cardiac muscle - following a myocardial infarctio, no regeneration is possible, just scarring. This is becauses myocytes are permanent cells - terminally differentiated and so can’t divide. The contractile cardiac myocytes are replaced by inflexible collagen which affects the contraction. This results in arrhythmias or cardiac failure leading to fluid accumulation.
Brain / CNS- Liquefactive necrosis left with cystic space – no fibrous scarring because wouldn’t have any connections, instead astrocytes proliferate to form a glial scar by gliosis. |
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Describe healing in bone, liver and peripheral nerves.
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Bone - Can repair completely from fracture by formation of haematoma inflammatory reaction capillary grow stem cell develop a callus which supported the framework
- Fracture damages blood vessels in periosteum and haversian systems - Fracture site fills will blood – haematoma - Angiogenesis occurs in the clot - Macrophages and osteoclasts migrate to site of injury and remove necrotic tissue - Osteoblasts and fibroblasts migrate and generate a callus – extracellular matrix which is mineralized – calcium hydroxyapatite crystals - The callus is woven bone and is remodelled to become mature laminar bone Bone must bear weight in order to return to original strength, calcium supplements help, nicotine damages recovery. Liver - Hepatocytes are stable cells which can enter the cell cycle if triggered to proliferate. You can remove 70% of the liver and it can still regenerate. Peripheral nerves - (wallerian degeneration) where damage is distal, regeneration begins at 3/4 days, regrowth down previous channels. Wallerian nerve degeneration - nerves regenerate to previous node of Ranvier and then axon regrows down the path it took previously, no cell division actually occurs - nerve growth only requires cytoplasm and membrane. |
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Describe regenerative capacity of cartilage, kidney, smooth and skeletal mucle.
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Cartilage – can regenerate
Kidney – epithelium regenerates, architecture cannot, produces glomerular scarring and loss of filtration capacity Smooth Muscle – can proliferate Skeletal Voluntary muscle – limited regenerative capacity from satellite cells |
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Define haemostasis:
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Haemostasis is the natural ability to arrest bleeding by vasoconstriction and coagulation or by surgical means ( ligating of blood vessels)
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What does Haemostasis depends on?
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- vessel walls
Vasoconstriction to limit blood loss - Platelets Adhere to damaged vessel wall and each other to form a platelet plug – regulated by thromboxane ( arachydonic acid) This is called primary haemostasis!! - coagulation system - fibrinolytic system |
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Why does there need to be a balance of coagulant and anti coagulant factors in the blood?
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There needs to be a balance of coagulant and anti coagulant factors in the blood as 1ml of blood can generate enough thrombin to convert all fibrinogen into fibrin.
Tight regulation is required. |
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Describe the blood clotting cascade, including intrinsic and extrinsic factors.
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The blood clotting cascade is triggered by damage to blood vessels and tissue damage and factors are released into blood, which trigger an amplified cascade of proteolytic activation of inactive components to active components, resulting in:
prothrombin thrombin which activates fibrinogen fibrin. Intrinsic pathway - triggered by endothelial damage - involves factors 12,11,9,8 - APTT –activated partial pressure thrombosis time - Warfarin inhibits Vit K which is needed in synthesis of factors 2, 7 ,9 , 10 Therefore warfarin inhibits the intrinsic pathway Extrinsic pathway - Tissue damage – acticated tissue factor 3 - Involves factor 7 ( triggered by tissue factor 3) - Prothrombin time measured in blood - Warfarin affects synthesis of factor 7 so inhibits extrinsic and intrinsic pathways |
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Describe the role of platelets.
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Platelet release reaction: primary
Platelets are activated by ADP and thromboxane A2 to aggregate to each other and adhere to the collagen that is exposed by the endothelial damage (localised clotting). Fibrinogen and VWF ( von willebrand factor) are connecting agents which help the platelets aggregate and form the platelet plug. Fibrin formed by the blood clotting cascade strengthens the clot |
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How may aspirin prevent platelet aggregation.
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Aspirin is an NSAID which inhibits cyclo-oxygenase thus preventing the conversion of arachydonic acid into prostaglandins and then prostaglandins into thromboxane by thromboxane synthase. Without thromboxane, platelet aggregation is not activated.
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What is the role of endothelial cells in haemostasis?
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ENDOTHELIAL CELLS – promote and inhibit haemostasis
Under normal conditions endothelial cells prevent platelet activation by secreting anti-thrombotic chemicals: plasminogen activators, nitric oxide, prostacylin and ADPase. The endothelial cells are usually attached to underlying collagen (IV) in basement membrane via von willebrand factors. Collagen is usually not exposed to the bloodstream. In endothelial damage, collagen, VWF and tissue factors are exposed to the blood stream which activates aggregation of the platelets. |
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Describe mechanisms for regulation of clot formation and breakdown.
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Regulation:
- Inactive zymogens in low concentration to prevent accidental activation - Amplication of small signal - Positive feedback by thrombin Break down: Thrombin destroys factors 5 (both pathways) and 8 ( intrinsic pathway). There are also many thrombin inhibitors: - Anti- thrombin 3 Heparin activates Inherited deficiency thrombosis - Alpha 1 anti-trypsin - Apha 2 macroglobulin Proteolytic deactivation: Protein C and S - Thrombin binds to endothelial receptors -> activation of protein C -> degrades factors 8 and 5. - Inherited deficiency of protein C/S may cause thrombosis – THROMBOTIC DISEASE! If thrombosis found in youth with no risk factor for thrombosis, it is likely to be an inherited disease. Fibronolysis: plasminogen -> plasmin by plasminogen activators found on endothelial cells: streptokinase and TPA (tissue plasmininogen activator) Plasmin breaks down fibrin and thus breaks down clot. Enzymes such as streptokinase and Tpa are plasminogen activators which are used as treatment of MI and in large PE. |
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Define thrombosis.
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Thrombosis is the formation of a solid mass of blood within the circulatory system DURING LIFE!!!
- clots often form post mortem, important to differentiate if they occur in life or death and so if they are the cause of death - activation of blood clotting cascade under pathological situations |
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Describe how thrombosis if caused.
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Thrombosis is caused by abnormalities in one or more of the following – virchow’s triad:
1. blood vessel wall atherosclerosis is usually the cause in arteries ( calcified vessels – crack on systole – expose lipids) direct injury inflammation 2. blood flow stagnant – veins – slow moving turbulent – arteries –lamina flow disturbed ( cells in the middle, plasma at edge) 3. blood components smokers – nicotine activates platelets post partum – tearing of vessels more clotting factors released feedback mechanism post operation – blood loss, damage feedback mechanism immobile during surgery so DIT likely to occur DURING surgery ( give heparin before if old) polycythemia – too many red blood cells but not enough to be leukaemia, - overactive bone marrow |
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describe the appearance and effects of thrombi in arterial and venous blood.
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ARTERIAL: fast flowing vessels – may be turbulent
Appearance: - pale ( fewer RBC trapped) - granular ( more fibrinogen in thrombus) - lines of zahn ( waves of thrombin) - lower cell content Arterial effects: - Ischaemia ( in heart – angina no cardiac enzymes released) - Infarction ( in heart cardiac enzymes are released - Depends on site and collateral circulation – if present and how good. VENOUS - soft and gelatinous ( less fibrin) - deep red ( more RBC trapped due to stagnant flow) - higher cell content Venous effects: - Congestion ( abnormal accumulation of blood ) - Oedema - Ischaemia - Infarction ( If tissue pressure due to oedema becomes too high, vessels can’t fill – red infarct) List predisposing factors for thrombosis. - Age - Immobility/bed rest - Smoking – nicotine - Operation – DVT - Pregnancy - Oral contraceptive |
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Describe the outcomes of thrombosis:
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Lysis: complete breakdown of thrombus by the fibronolytic system. Blood flow re-establised. Lysis is most common if thrombi are small.
Embolism: part of the thrombus breaks off and travels through the bloodstream and lodges in a small vessel at a distal site. Propagation: progressive spread of thrombosis in direction of flow ( distally in arteries and proximally in veins – back to heart). More propagation, more risk of pulmonary embolism PE. Organisation: repair process causes ingrowth of fibroblasts and capillaries – similar to granulation tissue. This lumen remains obstructed. Recanalisation: one or more channels formed through organisation and so blood flow through the vessel is re-establised, but usually incompletely. |
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Define and embolism.
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An embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin.
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Describe different types of embolism: thrombo, air, amniotic, fat.
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Thrombi emboli
- More than 90% of emboli are thrombi-emboli: - from systemic circulation, passes via vena cavae into right atria and ventricle and into pulmonary artery – pulmonary emboli (PE) - thrombus in heart, the emboli passes via the aorta to the renal, mesenteric and other arteries - thrombi in atheromatous carotid arteries, break up and emboli pass to the brain - thrombi in atheromatous abdominal aorta pass to arteries of the legs Air embolism - head and neck surgery - intravenous injections enough air to fill heart - BENDS – nitrogen embolism – coming up from water too quickly Amniotic embolism - Very rare – can cause DIC – disseminated intravascular coagulation - Amniotic fluid, fetal cells, hair and other debris enter maternal circulation causing an allergic reaction - Results in cardio-respiratory collapse Fat embolism - Fractures of long bones ( yellow marrow) - Lacerations of adipose tissue - Biochemical disturbance?? - Rash, shortness of breath confusion Tumour cells Metastasis – active process Medical equipment |
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List the predisposing factors for thrombosis.
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- Age
- immobility/bed rest Contraction of calf muscle needed for venous return - During operation – DVT - Smoking - nicotine - pregnancy and post partum - oral contraceptives Platelet aggregation - Severe burns Dehydrated immobile - Cardiac failure Fluid loss eg in legs poor venous return - Disseminated cancer ( spread throughout an organ of the body) Release agonists of intrinsic pathway |
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How can DVT be prevented?
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- Before surgery heparin is given which activates anti thrombin III and thus prevent thrombosis
- Leg compression during surgery and times of immobility/bed rest – TED socks If DVT develops intravenous heparin and oral warfarin are given. Warfarin also prevents the formation of further clots but does this much more slowly as it only affects the synthesis of factors. It inhibits vitamin K which is needed in the formation of factors 2, 7, 9, 10. ( vit k carboxylates glutamic acid to form gamma carboxyglutamate, calcium is also required for adherence to endothelial wall) |
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Describe the different types of pulmonary embolism.
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- Massive PE
> 60% reduction in blood flow – rapidly fatal Surgery and Streptokinase may be given - Major PE Medium sized vessels blocked Patients short of breath Cough and blood in sputum - Minor PE Small peripheral pulmonary arteries blocked Asymptomatic or mild shortness of breath Recurrent minor PEs lead to pulmonary hypertension |
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Describe haemophilia A including laboratory findings.
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Haemophila A is the most common type of haemophila. It is an X linked recessive genetic disorder which affects the production of factor 8.
Less than 1% factor 8 bleeding into joints (haemarthrosis) bleeding into muscles 1-5% of factor 8 prolonged bleeding after trauma Laboratory findings: - Bleeding time ( platelet time) – NORMAL ( platelets are not usually involved in blood clotting cascade conditions) - Prothrombin time – extrinsic – factor 7 – NORMAL - Activated Partial Pressure Time (APTT) – intrinsic –factor 12,11,9,8 – PROLONGED Treat the patient with intravenous factor 8!! (in the past blood was given – transmitted HIV) |
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Describe Disseminated intravascular coagulation – DIC: causes, laboratory findings, treatment,
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Lots of blood clots develop all over the body so that all fibrinogen is used up. Therefore when blood clotting factors are needed, there aren’t enough and bleeding occurs
Causes of DIC: - The most common cause is amniotic embolism – fetal debris triggers clotting cascade. - Systemic infections( septicaemia) - meningococcal septicaemia – gram negative diplococcic. - Endotoxic shock – endotoxins released from gram negative organism – meningococcal – activates factors. - malignancy Laboratory findings: - Prolonged prothrombin time – extrinsic pathway not working –FACTORS USED UP! - Prolonged activated partial thromboplastin time ( APTT) – intrinsic pathway not working – FACTORS USED UP - Prolonged thrombin clotting time – bottom part of pathway not working - Low plasma fibrinogen levels – used up to make fibrin - Very low platelets - Very high FDP – fibrin degradation products including D- dimers Treatment: - Anticoagulants - Platelets - Plasma – replenish coagulation factors and anti-thrombotic factors - Very grim prognosis – DIC – death is coming |
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What are D dimmers?
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D dimmers are fibrin degradation products that can be measured in the blood to investigate disorders of coagulation.
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Describe thrombocytopenia
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Thrombocytopenia occurs when there are too few platelets in the blood due to the bone marrow not making enough eg leukaemia or the platelets being destroyed eg DIC. There are many causes including infection eg sepsis, autoimmune diseases eg SLE, idiopathic causes eg idiopathetic thrombocytopenic purpura & drugs eg alcohol.
Thrombocytopenia may result in purpura, bruises particular on the arm caused by bleeding ( bigger than petechia) nose bleeds, bleeding gums and petechia – pinpoint haemorrhages on skin and mucous membranes. |
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Describe causes of thrombocytopenia.
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The bone marrow may not produce enough platelets as seen in:
- Leukaemia – white blood cells produced at expense of other cells in the bone marrow Very unwell - Sepsis, systemic viral or bacterial infection - Anaemia Vitamin B12 or folic acid deficiency anaemias - Lymphoma – cancer of lymphatic cells - Heavy alcohol consumption - Decreased production of thrombopoetin from the liver Platelets entrapped in enlarged spleen: - Cirrhosis with congestive splenomegaly - Gaucher’s disease - Myelofibrosis Dilution of platelets - Massive blood replacement or exchange transfusion with stored blood with too few platelets - Cardiopulmonary bypass surgery increased use or destruction of platelets: - Autoimmune diseases eg lupis - Idiopathic thrombocytopenic purpora Pinpoint bruises develop - Thrombotic thrombocytopenic purpora - Haemolytic uremic syndrome - HIV - DIC - Disseminated intravascular coagulation – can occur with amniotic embolism, malignancy, septicaemia - Drugs such as heparin, quinine, sulpha containing antibiotics, oral drugs for diabetes |
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Describe Thrombophilia.
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Thrombophillia is the increased tendency to thrombosis. It can be caused by inherited deficiencies in proteins in the fibrinolytic system or natural inhibitor proteins of the coagulation system:
- Protein C – degrades factors - Protein S - Anti-thrombin III ( what heparin activates) |
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Define atheroma.
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Atheroma is the accumulation of intracellular and extracellular lipid (and other materials) in the intima and media of large and medium sized arteries.
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Define atherosclerosis.
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Atherosclerosis is the thickening and hardening of arterial walls as a consequence of atheroma.
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Define arteriosclerosis
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Arteriosclerosis if the thickening the walls of the arteries and arterioles usually as a result if hypertension or diabetes mellutis.
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Describe the normal arterial structure.
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- Intima – endothelium and sub endothelial connective tissue
- Internal elastic lamina - Muscular media - External elastic lamina – the larger arteries have more elastin for elastic recoil – maintain arterial pressure - Adventitia – CT |
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Describe the macroscopic features of an atheroma.
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The fatty streak
- Lipid deposits in intima - Yellow, slightly raised - Caused by accumulation of foam cells - Might not be atheromatous The simple plaque - Raised yellow/white - Irregular outline - Widely distributed - Enlarge and coalesce ( fuse) The complicated plaque - Thrombosis – change in virchows triad – plaque fissue ( break down of fibrous cap and endothelium over plaque – exposed collagen) - Haemorrhage into plaque – vasa vasorum damaged - Calcification – seen in x rays - Aneurysm formation – severe atheroma in the intima -> thinning of the media -> loss of smooth muscle cells and elastic fibres -> replacement by non-contractile inelastic collagen -> permanent dilated artery – commonly abdominal aorta. |
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List common sites of atheromatous formation.
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- Aorta – especially abdominal
- Coronary arteries – white infarct - Carotid arteries – emboli in brain - Cerebral arteries - Leg arteries |
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Describe the microscopic features of an atheroma.
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Early features – the composition of a plaque ( macrophages, muscle cells, lipid and collagen)
- Proliferation of smooth muscle cells - Accumulation of foam cells – macrophage derived cells which have engulfed LDLs – form fatty streak in plaque - Extracellular lipid Later features - Fibrosis and Necrosis - Cholesterol clefts – cholesterol crystals deposited in tissues - May or may not be inflammatory cell infiltration - Internal elastic lamina is damaged causing damage in media - Ingrowth of blood vessels which are not well formed -> haemorrhage - Plaque fissuring – the breakdown of the fibrous gap and endothelium over the atheromatous plaque, exposing collagen fibres to the platelets initiating formation of thrombus. |
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Describe the clinical effects of atheromas.
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Ischaemic heart disease
- Coronary atheroma – sudden death - Myocardial infarction - white infarct - Angina pectoris - Arrhymias – necrotic tissue replaced by scar tissue – less contractile - Cardiac failure - necrotic tissue replaced by scar tissue – less contractile Cerebral ischaemia - Transcient ischaemic attack (TIA) syncope - Cerebtal infarction ( stroke) – red infarct - Multi-infarct dementia Mesenteric ischaemia – mesentery – peritoneum - Ischaemic colitis – ( inflammation of colon) -> ulcerative colitis -> bleeding - Malabsorbtion - Intestinal infarction Peripheral vascular disease - Intermittent claudication – pain in calf on walking due to iscaemia, goes away at rest – diminishing ability eg 100yrds first time, rest, 50 yards. - Leriche syndrome – occlusion of abdominal aorta and or both of the iliac arteries causing claudication in the buttocks and thighs and impotence. - Ischaemic rest pain - Gangrene - amputation Abdominal aortic aneurysm - aortic dissection -> rupture -> haemorrhage -> hypovolumic shock |
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List the predisposing risk factors for atherosclerosis
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Age
Gender - women protected before menopause hyperlipidaemia eg familial dyslipidaemia - high plasma cholesterol associated with atheroma - LDL most signicant, HDL protective Diabetes mellitus Alcohol – more than 5 units per day Infection – helicobacter pylori, Chlamydia pneumonia, cytomegalovirus Smoking – nicotine increases platlet aggregation, reduced prostaglandin synthesis Hypertension – damages endothelium Lack of exercise, obesity, oral contraceptive, stress, soft waterr |
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Describe the different types of lipoproteins.
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Lipoproteins carry lipid in the blood. The hydrophobic core contains varying amounts of cholesterol esters and TAGs and the hydrophilic surface coat is comprised of phospholipids, cholesterol and apoproteins ( a – e)
Chylomicrons – transport lipid from intestine to liver VLDL - carry cholesterol and TAGs from liver. The removal of TAGs forms LDL. LDL – rich in cholesterol, carries cholesterol to non-liver cells HDL – carries cholesterol from periphery back to liver. |
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Describe some risk markers for atheroma.
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Apoprotein E
- Genetic variations in Apo E are associated with changes in LDL levels. Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes. Polymorphisms can be used as risk markers for atheroma. Angiotensin converting enzyme (ACE) - High levels of this enzyme cause vasoconstriction and increase sodium and water reabsorbtion at the kidneys thus increase hypertension -> leading to damaged endothelium. |
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Describe the function of ACE inhibitors.
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• ACE catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor
• ACE degrades bradykinin, a potent vasodilator, and other vasoactive peptides These two actions make ACE inhibition a goal in the treatment of conditions such as high blood pressure, heart failure, diabetic nephropathy, and type 2 diabetes mellitus. Inhibition of ACE (by ACE inhibitors) results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, leading to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotension II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume |
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Describe familial hyperlipidaemia ( type IIa)
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Famillal hyperlipidaemia is a genetic predetermined abnormality of lipoproteins, high levels of LDLs.
- Defective LDL receptors - Insufficient number of LDL receptors – not expressed - LDLs don’t lie in the coated pit but irregularly placed along endothelium – defective receptors on coated pit for LDL receptors. - LDL metabolism increased. Familial hyperlipidaemia leads to early development of atheroma. It has associated physical signs - Arcus – corneal arcus - white ring of phospholipid and cholesterol around periphery of eye. - xanthomas – around body - fatty yellow deposits in tendon, elbow, palm - Xanthelasma – fatty deposits in medial corners of eye. |
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List the processes and cells involved in atherogenesis.
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- Thrombosis
- Lipid accumulation - Production of extracellular matrix - Interactions between cell types Cells: endothelial cells, platelet cells, smooth muscle cells, macrophages, lymphocytes, neutrophils. |
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Describe the hypothesis for atherogenesis.
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Endothelial injury due to: hypetension, raised LDLs, toxins eg cigarette stress and haemodynamic stress.
Endothelial – key to haemostasis, alter permeability to lipoproteins, secretion of collagen – platelet agregation, stimulation of proliferation and migration of smooth muscle cells. Platelets – key to haemostasis, stimulate proliferation and migration of smooth muscle cells (PDGF) Smooth muscle cells – take up LDL to become foam cells, synthesise collagen Macrophages – oxidise LDL, take up lipids to become foam cells, secrete proteases which modify matrix, release cytokines which stimulate proliferation and migration of smooth muscle cells Lymphocytes – secrete TNF which stimulates proliferation and migration of smooth muscle cells Neutrophils – secrete proteases leading to continued local damage and inflammation Endothelial injury due to LDL/toxins/hypertension, causes platelet adhesion, PDGF release = SMC proliferation and migration, LDL oxidation, uptake of lipid by SMC and macrophages, SMC produce matrix, foam cells produce cytokines causing further SMC stimulation and increased recruitment of inflammatory cells. |
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Describe prevention and intervention and of atheromas.
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Prevention: no smoking, reduced fat intake, treat hypertension, not too much alcohol, regular exercises/ weight control
Intervention: stop smoking, modify diet, treat hypertension, treat diabetes, lipid lowering drugs. |
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Describe the effects of sympathetic activity on the heart ie raised Camp.
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Myocardium:
Noradrenalin binds to b1 adrenoreceptors on myocardium which are GPCRs. G-alpha s activates adenylyl cyclase which increases camp levels. CAMP is a secondary messenger that activates PKA which phosphorylates VOCC, ryanodine receptors on SR and phospholamban. - VOCC – opened -> influx of extracellular calcium – increase force of contraction - Ryanodine – opened - influx of stored calcium – increase force of contraction - Phospholamban – inhibitor of SERCA, phosphorylation deactivates it so SERCA are opened and more calcium is stored for next heart beat Pacemaker potential - increased Camp activates IF channels so increases leak of sodium and potassium ions so depolarisation is achieved faster, steeper slope and heart rate increases. |
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Describe ANS effects on vasculature.
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Most vessels receive sympathetic innervations, controlled from the hindbrain via the vasomotor centres in the medulla oblongata.
There are exceptions eg erectile tissue receives parasympathetic innervations (point and shoot) Most arteries and veins have a1 receptors. The vasculature of myocardium, liver and skeletal muscle also has b2 adrenoreceptors. Circulating adrenalin has a higher affinity for b2 adrenoreceptors. Vasomotor tone: constant ANS innervations. - Increased sympathetic output – vasoconstriction Increased calcium intracellular concentration from stores and via influx from extracellular concentration smooth muscle contraction - Normal sympathetic output – vasomotor tone Vasomotor tone is the constant level of nervous stimulation to the muscles in the blood vessel walls Gives the muscles a resting level of contraction - Decreased sympathetic output – vasodilation Activated b2 adrenoreceptors - qs however causes bronchodilation |
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Describe the role of local metabolites.
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Active tissues produce more metabolites eg H+ ions, adenosine, K+, CO2.
Local increases in metabolites have a strong vasodilator effect. This is more important for ensuring correct perfusion of skeletal and cardiac muscle than activation of B2 receptors ( vasorelaxation) In skeletal muscles, vasomotor tone is high at rest but in exercise is antagonised by local vasodilator metabolites. In the gut vasomotor activity is high until a meal is consumed, causing release of local metabolites. |
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How is parasympathetic and sympathetic activity to the heart and blood vessels controlled?
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Both parasympathetic and sympathetic outflow to the heart are controlled by centres in the medulla oblongata which receive information from the sensory receptors detetecting blood pressure ( baroreceptors) and higher centres in the CNS.
High pressure – baroreceptors stimulated and communicate with CNS -> trigger parasympathetic activity! - Nerve endings in carotid sinus and aortic arch are sensitive to stretch - Increased arterial pressure stretches these receptors Low pressure – atrial receptors communicate with CNS -> trigger sympathetic activity, |
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Describe the different drugs acting on neurotransmitter receptors.
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Sympathomimetics:
- Adrenaline is not selective, acts on all adrenoreceptors. It is administered to restore function in cardiac arrest and for anaphylactic shock. - Dobutamine may be given in cardiogenic shock – pump failure. B1 agonist - Salbutamol for treatment of asthma – B2 agonist Adrenoreceptor antagonists - Alpha adrenoreceptor antagonists: Anti hypertensive agent – causes vasodilation by inhibiting action of noradrenalin. - Beta adrenoreceptor antagonists PROPANOLOL is not selective between B1 &B2. Slows heart rate and reduces force of contraction ( B1 ). Causes bronchoconstriction ( B2) ATENOLOL – B1 selective – slows heart rate, less risk of bronchoconstriction. Cholinergics: Muscarinic agonists : MUSCARINE - Eg pilocarpine - Used in treatment of glaucoma -> Constricts pupillae muscle Muscarinic antagonists: ATROPINE - Lowers parasympathetic activity of muscles and gland thus Increases heart rate and bronchial dilation - Used to dilate pupils for examination of eye. - Used to treat extreme bradycardia Nicotine agonists (mimics) - NICOTINE - Increases receptor activity Nicotinic agonists - Curare ( arrow poisons) - Muscle relaxant used in anaesthesia during an operation or facilitating intubation of the trachea - Competitive inhibitor: Can be overcome by acetylcholinesterase inhibitor, increasing the amount of acetylcholine available in the synaptic cleft - Depolarising agonist – desensitizes receptor, higher affinity than Ach. |
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Describe the effects of sympathetic innervations on organs.
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Pupil of eye – A1 adrenoreceptor – dilation by contraction of radial muscle
Glands ( nasal, lacrimal, salivary, gastric, pancreas) – a1/b adrenoreceptors - Inhibits secretory activity ( causes vasoconstriction of blood vessels supplying gland). Dry mouth. Diarrhoea due to mucous secretions setting up an osmotic potential and causing water to flow out into the GI tract. Airways of the lungs – B2 – relaxation Heart SA node – B1 – increases heart rate Heart atrial muscle – B1 –increase force of contraction Heart ventricular muscle – B1 – Increase in force of contraction Blood vessels in most tissues – A1 – vasoconstriction Blood vessels in skeletal muscle – B2 – vasoconstriction Blood vessels in erectile tissue – A1 – constriction Gut secretion – no effect Gut motility – decreases peristalysis – A1, A2, B2 Gut sphincters – constriction – A2, B2 Adipose tissue – B3 – increased lipolysis Liver – A1 – increased glycogenolysis B2 – gluconeogenesis Kidney – B1 -rennin secretion Sweat glands – M3 – secretion Sweat glands in palms of hands – A1 – localised secretion Male sex organs – A – ejaculation Bladder – B2 – relaxes detrusor muscle ( filling). A1 – contracts sphincter ( prevents emptying) |
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Describe the effects of parasympathetic innervations on organs.
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Pupil of eye - M3 – contraction of sphincter muscle
Glands ( salivary, lacrimal, nasal, gastric, pancreas) – M3 – increased secretion Airways of lungs – M3 – bronchoconstriction Heart SA node – M2 – decreased heart rate Heart ventricular and atrial muscle – no effect!! Blood vessels in most tissues – NO EFFECT Blood vessels in erectile tissue – M3 – dilation Gut – M3 – Increased secretion, increased motility, relaxation of sphincters – increased peristalysis Adipose tissue – storage Male sex organ – M3 – erection Bladder – contracts detrusor muscle, relaxes sphincter – M3 |
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If you gave an individual an injection of adrenaline, what would happen.
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Adrenaline is a sympathomimetic which is not sensitive and can bind to all adrenoreceptors, mimicking sympathetic innervations. It increases heart rate, increases force of heart contraction, and increases sweating and increases gluconeogensis, glycogenolysis, and lipolysis. It also causes bronchodilation and vasodilation of coronary arteries and vessels in skeletal muscle.
Adrenaline is used to treat cardiac failure and anaphylactic shock. |
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What would an individual with a high circulating titre of adrenaline look like to an outside observer.
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Pale (vasoconstriction), sweating, hyperventilation, dilated pupils, hyperactive.
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Why does your mouth go dry when you are frightened.
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Sympathetic fibres are activated and they increase the viscosity of the saliva by retaining water.
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If sympathetic activity generally reduces gut motility why do many people get the runs if they are nervous.
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Mucous secretions in the GI tract then establish an osmotic gradient, so that water moves out into GI tract causing diarrhoea.
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List the physiological effects of a posison which inactivates acetylcholinesterase.
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Eg organophosphates.
Constant parasympathetic innervations of M receptors. - Bradycardia – death, bronchoconstriction, vasodilation, prolonged muscle contraction, respiratory paralysis, increased GI motility. The individual will look pale, weak, difficulty breathing, nose and mouth secretions, tears, eventual paralysis. Respiratory paraslysis is the most life threatening, Atropine can be given if poisoned as it blocks the muscarinic receptors. |
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Describe the The autonomic nervous system: sympathetic, parasympathetic, enteric.
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The autonomic nervous system: the divisions usually work together to maintain balance and often have opposite effects
- Sympathetic Fight, flight and fright UNDER STRESS – more dominant Sympathetic drive to different tissues is independently regulated eg activity to heart can increase without activity to GI tract increasing, in stress a more co-ordinated response. - Parasympathetic Rest and digest UNDER BASAL CONDITTIONS – more dominant - Enteric Network of neurones surrounding GI tract Controlled via sympathetic and parasympathetic neurones Exerts control over smooth muscle ( vascular and visceral), exocrine secretion and rate and force of contraction of the heart. |
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Describe the structure of ANS.
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2 neurones, 1 preganglionic in the CNS and 1 postganglionic in the PNS.
Sympathetic : - Preganglion neurone is shorter than in parasympathetic - Originates from thoracolumbar region (T1-L2) - Most synapses in the paravertebral chain of ganglia – at same level or above/below - Some ganglia are located in the neck and abdomen – longer pre-ganglionic neurones Parasympathetic: - Preganglionic neurone is longer than in sympathetic - Originates from craniosacral region ( cranial – III,VII,IX,X & S2-S4) - Synapses with neurones in ganglia close to the target tissue or in the target tissue |
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Describe Neurotransmitters and receptors in the ANS.
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Preganglionic neurones in both ANS divisions release Ach into synaptic cleft where it crosses and binds to a nicotinic Ach receptors on the postganglionic neurone.
The nicotinic ACh receptor is a ligand gated ion channel ( allows sodium in and potassium out – depolarises membrane – action potential if threshold reached) In Postganglionic neurones, the neurotransmitter released differs Sympathetic – noradrenalin –> adrenoreceptors ( A and B characterised by agonists and affinity to antagonists) - Exception – innervations of sweat glands – acetylcholine is released and acts on muscarinic receptors ( sweat glands are only innervated by sympathetic division) - Chromafin cells of the adrenal medulla are like specialised postganglion sympathetic neurones except they release adrenalin which circulates in the blood stream Parasympathetic –cholinergic – releases acetylcholine which binds to muscarinic Ach receptors. |
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Describe adrenoreceptors
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Noradrenalin and adrenalin act on adrenoreceptors. There are many variations of adrenoreceptors and different tissues can have different subtypes allowing for diversity of action and selectivity of drug action. The receptors are G protein coupled receptors – no integral ion channel or enzyme – signal transduction. - Alpha adrenoreceptor Alpha 1 – Gq – activates phospholipase ( vasoconstriction) Alpha 2 – Gi – inhibits adenylyl cyclase, opens K+ channels ( - Beta adrenoreceptor Beta 1 - Gs – activates adenylyl cyclase -> increased cAMP -> PKA – open VOCC ( heart) Beta 2 – airways of lungs – relaxation by SNS |
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Describe Muscarinic Ach receptors.
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Muscarinic receptors are found on the effector cells in parasympathetic innervations. They bind to acetylcholine. They are G protein coupled channels and have no integral ion channel
- M1 – Gq – phosphorlipase C - - M2 – Gi - inhibits adenylyl cyclase and increase K+ conductance –ve chronotrophic effect. - M3 – Gq – phospholipase C - airways – contraction |
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How is the cardiovascular system controlled by nervous stimulation?
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The ANS controls: The heart rate, the force of contraction and the resistance of peripheral blood vessels ( vasomotor tone).
The heart rate, controlled by the SA node, would be 100bpm without constant parasympathetic tone which brings it down to 60bpm. Parasympathetic control: - 10th cranial nerve = vagus nerve - Post ganglionic neurone releases acetylcholine which acts on M2 receptors at SA and AV nodes -> Gi -> increased K+ conductance – prolonged action potential. SA node: Decreases heart rate by targeting SA node (-ve chronotrophic effect) AV node: Decreases AV node conduction velocity Sympathetic activity increases pacemaker potential and force of contraction. - Postganglionic fibres from the sympathetic trunk - Innervates SA node AV node and myocardium - Releases noradrenalin -> B1 – increases heart rate and force of contraction |
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describe atheroma formation.
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Damage to the endothelium is caused by LDLs/ toxins/ hypertension. LDLs penetrate intima, become oxidised and are absorbed by macrophages which become foam cells. when foam cells dies they produce the fatty streak - yellow, lipid deposits in intimia. Macrophages produce cytolkines which stimulate the proliferation of smooth muscle cells from the media and the migration to the intima. The smooth muscle cells produce the extracellular matrix.
Cytokines also recruit inflamatory cells. The media thickens causing aneurhysm until it can't any more and so the lumen narrows. Plaque fissure exposes collagen fibres to the blood triggering platelet activation and clot formation. The thrombus can break off as emboli. |
